WO2022128843A1 - Dihydrofuropyridine derivatives as rho- kinase inhibitors - Google Patents

Dihydrofuropyridine derivatives as rho- kinase inhibitors Download PDF

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Publication number
WO2022128843A1
WO2022128843A1 PCT/EP2021/085367 EP2021085367W WO2022128843A1 WO 2022128843 A1 WO2022128843 A1 WO 2022128843A1 EP 2021085367 W EP2021085367 W EP 2021085367W WO 2022128843 A1 WO2022128843 A1 WO 2022128843A1
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WIPO (PCT)
Prior art keywords
methyl
pyridin
aminopyrimidin
amino
dihydrofuro
Prior art date
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PCT/EP2021/085367
Other languages
French (fr)
Inventor
Fabio Rancati
Alessandro ACCETTA
Anna Maria Capelli
Daniele PALA
Christine Edwards
Adele Elisa PASQUA
Prashant Bhimrao Kapadnis
Arnaud Jean Franҫois Auguste CHEGUILLAUME
David Edward Clark
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Chiesi Farmaceutici S.P.A.
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Publication date
Priority to US18/267,177 priority Critical patent/US20240092790A1/en
Priority to IL303641A priority patent/IL303641A/en
Priority to CN202180084240.2A priority patent/CN116600811A/en
Priority to EP21824584.3A priority patent/EP4263548A1/en
Priority to KR1020237023625A priority patent/KR20230121809A/en
Priority to CA3202146A priority patent/CA3202146A1/en
Application filed by Chiesi Farmaceutici S.P.A. filed Critical Chiesi Farmaceutici S.P.A.
Priority to AU2021402526A priority patent/AU2021402526A1/en
Priority to MX2023005867A priority patent/MX2023005867A/en
Priority to PE2023001862A priority patent/PE20231658A1/en
Priority to JP2023536034A priority patent/JP2023552899A/en
Publication of WO2022128843A1 publication Critical patent/WO2022128843A1/en
Priority to CONC2023/0009444A priority patent/CO2023009444A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to novel compounds inhibiting Rho Kinase (hereinafter ROCK Inhibitors); methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
  • ROCK Inhibitors novel compounds inhibiting Rho Kinase
  • the compounds of the invention are inhibitors of the activity or function of the ROCK -I and/or ROCK-II isoforms of the Rho-associated coiled-coil forming protein kinase (ROCK).
  • ROCK Rho-associated coiled-coil forming protein kinase
  • Rho-associated coiled-coil forming protein kinase belongs to the AGC (PKA/PKG/PKC) family of serine-threonine kinases.
  • AGC PKA/PKG/PKC
  • ROCK-I also referred to as pl60 ROCK or ROKp or ROCK1
  • ROCK-II ROKa or ROCK2
  • ROCK-II ROKa or ROCK2
  • ROCK-II and ROCK-I are expressed in many human and rodent tissues including the heart, pancreas, lung, liver, skeletal muscle, kidney and brain (above Riento and Ridley, 2003).
  • ROCK activity is significantly higher in both lung tissues and circulating neutrophils as compared with controls (Duong-Quy S, Bei Y, Liu Z, Dinh-Xuan AT. Role of Rho-kinase and its inhibitors in pulmonary hypertension. Pharmacol Ther. 2013;137(3):352-64).
  • a significant correlation was established between neutrophil ROCK activity and the severity and duration of pulmonary hypertension (Duong-Quy et al., 2013).
  • ROCK reactive oxygen species
  • COPD chronic obstructive pulmonary disease
  • ARDS/ALI acute and chronic pulmonary diseases
  • selective inhibitors have the potential to treat a number of pathological mechanisms in respiratory diseases, such as smooth muscle hyper-reactivity, bronchoconstriction, airway inflammation and airway remodeling, neuromodulation and exacerbations due to respiratory tract viral infection (Fernandes LB, Henry PJ, Goldie RG. Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2007 Oct;l(l):25-33).
  • Rho kinase inhibitor Y-27632 causes bronchodilatation and reduces pulmonary eosinophilia trafficking and airways hyperresponsiveness (Gosens, R.; Schaafsma, D.; Nelemans, S. A.; Halayko, A. J. Rhokinase as a drug target for the treatment of airway hyperresponsiveness in asthma. Mini-Rev. Med. Chem. 2006, 6, 339-348). Pulmonary ROCK activation has been demonstrated in humans with idiopathic pulmonary fibrosis (IPF) and in animal models of this disease.
  • IPF idiopathic pulmonary fibrosis
  • ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis, thus indicating ROCK inhibitors as potential powerful pharmacological agents to halt progression of pulmonary fibrosis (Jiang, C.; Huang, H.; Liu, J.; Wang, Y.; Lu, Z.; Xu, Z. Fasudil, a rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. Int. J. Mol. Sci. 2012, 13, 8293-8307).
  • Rho Kinase Inhibitors See e.g. W02004/039796 disclosing phenylaminopyrimidine compounds derivatives; W02006/009889 disclosing indazole compound derivatives; W02010/032875 disclosing nicotinamide compounds derivatives; W02009/079008 disclosing pyrazole derivatives; WO2014/118133 disclosing pyrimidine derivatives and, of the same Applicant of the present invention, WO2018/115383 disclosing bicyclic dihydropyrimidine and WO 2018/138293, WO 2019/048479, WO 2019/121223, WO 2019/121233, WO 2019/121406, WO 2019/238628, WO 2020/016129 disclosing tyrosine-amide compounds derivatives and analogues.
  • the compounds disclosed exhibit substantial structural differences from the compounds of the present invention.
  • the present invention relates to novel compounds differing from the structures disclosed in the art at least for a common new core scaffold.
  • the invention relates to compounds that are characterized by the 2,3-dihydrofuro[3,2-c]pyridine moiety, particularly 2,3-dihydrofuro[3,2-c]pyridin-4- amine, particularly preferably N-(3-(((2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)phenyl)formamide and 3-(((2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)benzamide derivatives, which are inhibitors of ROCK-I and ROCK-II isoforms of the Rho-associated coiled-coil forming protein kinase (ROCK) that have therapeutically desirable characteristics, are particularly promising in the field of respiratory diseases but not excluding other fields such as that of immune system disorders including Graft-versus-host disease (GVHD), and for some pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary pulmonary
  • the compounds of the invention may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the compound of the invention are active as inhibitors of ROCK-I and ROCK-II isoforms, they are potent and have advantageously other improved properties such as selectivity and other in vitro properties indicative for a preferred route of administration.
  • SUMMARY OF THE INVENTION The present invention is directed to a class of compounds, acting as inhibitors of the Rho Kinase (ROCK), of formula (I) I Wherein the variables X 1 , X 2 , X 3 and X 4 , p, R, R 1 , L, n, R 2 and R 3, R 6 and R 7 are as defined in the detailed description of the invention; or pharmaceutically acceptable salts and solvates thereof.
  • ROCK Rho Kinase
  • the present invention refers to a compound of formula (I) for use as a medicament.
  • the present invention provides the use of a compound of the invention for the manufacture of a medicament.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of any disease associated with ROCK enzyme mechanisms, that is to say characterized by ROCK enzyme aberrant activity and/or wherein an inhibition of activity is desirable and in particular through the selective inhibition of the ROCK enzyme isoforms over other Kinases.
  • the present invention provides a method for prevention and/or treatment of any disease associated with ROCK enzyme mechanisms as above defined, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention are used alone or combined with other active ingredients and may be administered for the prevention and/or treatment of immune system disorders including Graft-versus-host disease (GVHD), and for pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH) and specifically pulmonary arterial hypertension (PAH).
  • GVHD Graft-versus-host disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • PH pulmonary hypertension
  • PAH pulmonary arterial hypertension
  • the term “Pharmaceutically acceptable salts” refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts of the invention comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.
  • Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, camphor sulfonic, acetic, oxalic, maleic, fumaric, succinic and citric acids.
  • solvates which are a further object of the invention.
  • Polymorphs and crystalline forms of compounds of formula (I), or of pharmaceutically acceptable salts, or solvates thereof are a further object of the invention.
  • Halogen or “halogen atoms” includes fluorine, chlorine, bromine, and iodine atom ; meaning Fluoro, Chloro, Bromo, Iodo as substituent.
  • (C 1 -C 6 )Alkyl refers to straight-chained or branched alkyl groups wherein the number of carbon atoms is in the range 1 to 6.
  • alkyl groups are for example methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methylbutyl and the like.
  • the expressions “(C 1 -C 6 )Haloalkyl” refer to the above defined “(C 1 -C 6 )alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other. Examples include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl groups.
  • (C 1 -C 6 )Hydroxyalkyl and “(C 1 - C 6 )aminoalkyl”refer to the above defined “(C 1 -C 6 )alkyl” groups wherein one or more hydrogen atoms are replaced by one or more hydroxy (OH) or amino group respectively, examples being hydroxymethyl and aminomethyl and the like.
  • the definition of aminoalkyl encompasses alkyl groups (i.e. “(C 1 -C 6 )alkyl” groups) substituted by one or more amino groups (-NR 8 R 9 ).
  • aminoalkyl is a mono-aminoalkyl group such as R8R9N-(C 1 -C 6 )alkyl.
  • the substituents R8 and R9 are defined as R 4 and R 5 in the above detailed description of the invention.
  • Derived expression such as aminoalkoxyl thus refer to the above define aminoalkyl linked to the rest of the molecule from the alkil side via an ether bridge, e.g. with linear representation -O-(CH 2 ) m NR 4 R 5 .
  • (C 3 -C 10 )cycloalkyl likewise “(C 3 -C 8 )cycloalkyl” or “(C 3 - C 6 )cycloalkyl” refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and polycyclic ring systems such as adamantan-yl.
  • Aryl refers to mono, bi- or tri-cyclic carbon ring systems which have 6 to 20, preferably from 6 to 15 ring atoms, wherein at least one ring is aromatic.
  • heteroaryl refers to mono-, bi- or tri-cyclic ring systems with 5 to 20, preferably from 5 to 15 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, S or O).
  • aryl or heteroaryl monocyclic ring systems include, for instance, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl radicals and the like.
  • aryl or heteroaryl bicyclic ring systems include naphthalenyl, biphenylenyl, purinyl, pteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzoimidazole- yl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothiopheneyl, benzodioxinyl, dihydrobenzodioxinyl, indenyl, dihydro-indenyl, dihydrobenzo[1,4]dioxinyl, benzothiazole-2-yl, dihydrobenzodioxepinyl, benzooxazinyl, 1,2,3,4-tetrahydroisoquinoline-6-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 4,5,6,7- tetrahydrobenz
  • aryl or heteroaryl tricyclic ring systems include fluorenyl radicals as well as benzocondensed derivatives of the aforementioned heteroaryl bicyclic ring systems.
  • the derived expression “(C 3 -C 10 )heterocycloalkyl” likewise “(C 3 -C 8 )heterocycloalkyl” or “(C 3 -C 6 )heterocycloalkyl” refers to saturated or partially unsaturated mono, bi- or tri- cycloalkyl groups of the indicated number of carbons, in which at least one ring carbon atom is replaced by at least one heteroatom (e.g.
  • heterocycloalkyl i.e. heterocyclic radical or group
  • Said heterocycloalkyl is further optionally substituted on the available points in the ring, namely on a carbon atom, or on an heteroatom available for substitution.
  • heterocycloalkyl examples include: oxetanyl, tetrahydro-furanyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one-yl, dihydropyrrolyl, 5-oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, octahydrocyclopenta[c]pyrrol-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyra
  • Aryl(C 1 -C 6 )alkyl refers to an aryl ring linked to a straight-chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. phenylmethyl (i.e. benzyl), phenylethyl or phenylpropyl.
  • Heteroaryl(C 1 -C 6 )alkyl refers to an heteroaryl ring linked to a straight-chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. furanylmethyl.
  • alkanoyl refers to HC(O)- or to alkylcarbonyl groups (e.g. (C 1 -C 6 )alkylC(O)-) wherein the group “alkyl” has the meaning above defined. Examples include formyl, acetyl, propanoyl, butanoyl.
  • alkoxy or “(C 1 -C 10 ) alkoxyl”, likewise “(C 1 -C 6 ) alkoxy” or “(C 1 -C 6 ) alkoxyl” etc., refers to a straight or branched hydrocarbon of the indicated number of carbons, linked to the rest of the molecule through an oxygen bridge.
  • (C 1 -C 6 )Alkylthio refers to the above hydrocarbon linked through a sulfur bridge.
  • the derived expression “(C 1 -C 6 )haloalkoxy” or “(C 1 -C 6 )haloalkoxyl” refers to the above defined haloalkyl, linked through an oxygen bridge.
  • An example of (C 1 -C 6 )haloalkoxy is trifluoromethoxy.
  • (C 3 -C 6 )heterocycloalkyl-(C 1 -C 6 )alkyl and “(C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl” refer to the above defined heterocycloalkyl and cycloalkyl groups linked to the rest of the molecule via an alkyl group of the indicated number of carbons, corresponding e.g. to linear formula (C 3 -C 6 )heterocycloalkyl- (CH 2 ) m - or (C 3 -C 6 )cycloalkyl-(CH 2 ) m- for example piperidin-4-yl-methyl, cyclohexylethyl.
  • (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl refers to the above defined alkoxy group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example methoxymethyl.
  • (C 1 -C 6 )haloalkoxy (C 1 -C 6 )alkyl refers to the above defined (C 1 -C 6 )haloalkoxy” group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example difluoromethoxypropyl.
  • bracketed group is a lateral group, not included into the chain, and brackets are used, when deemed useful, to help disambiguating linear chemical formulas; e.g. the sulfonyl group -SO 2 - might be also represented as–S(O) 2 – to disambiguate e.g. with respect to the sulfinic group –S(O)O–.
  • group –(CHR 3 ) n -R 2 herein is a linear representation of the terminal part of the charachterizing group found in formula (I) and (Ia).
  • (R)p) is absent, that is to say no substituent, other than H when needed, is present.
  • a bridging divalent group e.g. (CH 2 )n
  • the statement “n in each occurrence is zero...” or “n is 0” means that the bridging group is absent, that is to say it is a bond.
  • physiological acceptable anions selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p- toluenesulfonate, pamoate and naphthalene disulfonate may be present.
  • acidic groups such as COOH groups
  • physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions.
  • Compounds of formula (I) when they contain one or more stereogenic center may exist as optical stereoisomers. Where the compounds of the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. It is to be understood that all such single enantiomers, diastereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • the absolute configuration (R) or (S) for carbon bearing a stereogenic center is assigned on the basis of Cahn-Ingold-Prelog nomenclature rules based on groups’ priorities.
  • Single stereoisomer when reported near the chemical name of a compound indicate that the isomer was isolated as single diastereoisomer or enantiomer (e.g via chiral chromatography) but the absolute configuration at the relevant stereogenic center was not determined/assigned.
  • Atropisomers result from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers (Bringmann G et al, Angew. Chemie Int. Ed. 44 (34), 5384-5427, 2005. doi:10.1002/anie.200462661).
  • Atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).
  • Atropisomers differ from other chiral compounds in that in many cases they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible chemically. Separation of atropisomers is possible by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other.
  • Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other.
  • CBS Corey Bakshi Shibata
  • Racemic forms of compounds of formula (I) as well as the individual atropisomers (substantially free of its corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are included in the scope of the present invention.
  • the invention further concerns the corresponding deuterated derivatives of compounds of formula (I).
  • deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount above its natural abundance.
  • the percent of deuterium at that position is at least 90%, more preferably at least 95%, even more preferably 99%.
  • All preferred groups or embodiments described above and herebelow for compounds of formula (I) may be combined among each other and apply as well mutatis mutandis.
  • the present invention refers to compounds of general formula (I), acting as ROCK inhibitors, to processes for the preparation thereof, pharmaceutical compositions comprising them either alone or in combination with one or more active ingredient, in admixture with one or more pharmaceutically acceptable carriers.
  • the present invention is directed to a class of compounds of formula (I) I wherein X 1 , X 2 , X 3 and X 4 are all CH or one of X 1 , X 2 , X 3 and X 4 is N and the others are CH; p is zero or an integer from 1 to 4; each R, when present, is in each occurrence independently selected from (C 1 -C 6 )alkyl and halogen selected from F, Cl, Br and I; wherein preferably R is F, Cl or methyl; R 1 is pyrimidinyl, preferably pyrimidin-4yl, substituted by one or more group selected from -(CH 2 ) m NH 2 ; particularly preferably R 1 is 2-aminopyrimidin-4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R 2 and R 3 are in each occurrence independently selected from the group consist
  • the invention is directed to a compound of formula (I) wherein X 1 , X 3 and X 4 are all CH groups and X 2 is a CH group or a nitrogen atom; R 1 is 2-aminopyrimidin-4-yl; all the other variables being as defined above.
  • Said preferred group of compounds is represented by the formula (Ia) Ia
  • Particularly preferred are compounds of formula (I) as above defined, wherein X 1 , X 2 , X 3 , X 4 are all CH group; each R, when present, is in each occurrence independently selected from F, Cl, Br and I; wherein preferably R is F; R 1 is pyrimidinyl substituted by -NH 2 ; particularly preferably R 1 is 2- aminopyrimidin-4-yl; L is -C(O)NH-; n is 0 (i.e.
  • R3 is absent);
  • R 2 is in each occurrence independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkyl (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkoxy (C 1 -C 6 )alkyl, all the other variables being as defined above, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof.
  • Said particularly preferred group of compounds is represented by the formula (Ib)
  • Particularly preferred in this last embodiment is a compound of formula (Ib) wherein R 2 is selected from methyl, ethyl, propyl, 2-hydroxy-2-methylpropyl, 3- methoxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-isopropoxypropyl, 3-methoxy-3- methylbutyl, 2-methoxy-2-methylpropyl, 3-fluoropropyl, 2-fluoro-2-methylpropyl, 2,2- difluoropropyl, 3,3-difluoropropyl; all the other variables and substitution being as defined above, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof.
  • the invention is directed to a compound of formula (I) wherein X 1 , X 2 , X 3 and X 4 are all CH; p is zero or an integer from 1 to 4; each R, when present, is halogen in each occurrence independently selected from F, Cl, Br and I, wherein preferably R is F; R 1 is pyrimidinyl substituted by -NH 2 ; particularly preferably R 1 is 2- aminopyrimidin-4-yl; L is -C(O)NH-; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R 3 , when present, is H, and R 2 is selected from the group consisting of heteroaryl and (C 3 -C 6 )heterocycloalkyl, preferably R 2 is an heterocycloalkyl, each of which heteroaryl and heterocycloalkyl is in its turn optionally substituted with one or more groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alky
  • R2 is selected from , methoxypyridinyl, ((dimethylamino)ethoxy)pyridin-2-yl, (piperazinyl)pyridinyl, tetrahydrofuranyl, dimethyltetrahydrofuranyl, oxetan-2-yl; all the other variables and substitution being as defined above, or pharmaceutically acceptable salts and solvates thereof.
  • a further preferred group of compounds according to the invention are those of formula (I) wherein X 1 , X 2 , X 3 and X 4 are all CH or X 2 , is N and the others are CH; p is zero or 1; each R, when present, is F; R 1 is 2-aminopyrimidin-4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of -H, (C 1 -C 6 )alkyl which is methyl, propyl, isopropyl, tert-butyl, (C 1 -C 6 )hydroxyalkyl which is 2-hydroxy-2-methylpropyl, (C 1 -C 6 ) alkoxy (C 1 -C 6 )alkyl which is 3-methoxypropyl, 2-ethoxye
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients, either alone or in combination with one or more further active ingredient as detailed below.
  • the invention provides the compounds listed in the table below and pharmaceutical acceptable salts thereof.
  • the compounds of the invention including all the compounds hereabove listed, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or by using other known methods, reagents and starting materials.
  • a suitable protective group for intermediates requiring protection of a carboxylic acid can be C 1 -C 4 esters (PG 1 : methyl, isopropyl, tert-butyl or ethyl), preferably methyl.
  • a suitable protective group for intermediates requiring the amino group protection can be carbamates such as tert-butylcarbamate (PG 2 : tert-butoxycarbonyl or Boc), benzylcarbamate (PG 2 : Benzyloxycarbonyl or Cbz), ethylcarbamate (PG 2 : ethoxycarbonyl) or methylcarbamate (PG 2 : methoxycarbonyl), preferably PG 2 is Boc.
  • the compounds of formula (I), here reported again for clarity, including all the compounds here above listed, can be usually prepared according to the procedures shown in the schemes below. Where a specific detail or step differs from the general schemes it has been detailed in the specific examples, and/or in additional schemes.
  • Enantiomerically pure compounds can be prepared according to generally known reactions, e.g. according to the reactions described below, by means of enantiomerically pure starting materials and intermediates. These intermediates may be commercially available or readily produced from commercial sources by those of ordinary skill in the art.
  • enantiomerically pure compounds can be prepared from the corresponding racemates by means of chiral chromatography purification. Stereochemically pure compounds may be obtained by chiral separation from a stereoisomers mixture, or (whenever there are two or more stereogenic centres -i.e. chiral center- in compounds of formula (I)) stepwise by chromatographic separation of diastereoisomers followed by further chiral separation into single stereoisomers.
  • Compounds of formula (I) can be prepared according to scheme 1 starting from commercially available intermediate II or easily obtainable by those skilled in art.
  • Intermediate II can be converted into intermediate III by means of four consecutive steps including 1) chlorination, 2) amination, 3) reduction and 4) bromination.
  • the chlorination step may be carried out by refluxing intermediate II with an appropriate chlorinating agent (neat or in solution with an organic solvent such as DCM or dioxane) such as POCl 3 or SOCl 2 .
  • the amination step can be carried out by introducing a masked ammonia such as benzophenone imine through a Buchwald type palladium catalyzed reaction using, for example, tris(dibenzylideneacetone)dipalladium(0)/BINAP catalytic system followed by hydrolysis of the benzophenone imine by using hydroxylamine to give the corresponding furo[3,2-c]pyridin-4-amine.
  • the amination step can be carried out by introducing 4-methoxybenzylamine by means of S N Ar reaction (nucleophilic aromatic substitution) followed by deprotection with a strong acid such as trifluoroacetic acid or methansulphonic acid.
  • Reduction of furo[3,2-c]pyridin-4-amine to give 2,3- dihydrofuro[3,2-c]pyridin-4-amine can be carried out, for example, by hydrogenation of a solution of furo[3,2-c]pyridin-4-amine in methanol / acetic acid in the presence of a Pd/C catalyst under high H 2 pressure (e.g.10 bar) and at a temperature of 50oC or higher.
  • intermediate III can be obtained by means of bromination of 2,3- dihydrofuro[3,2-c]pyridin-4-amine (step 4) by reaction with a brominating agent such as N-bromosuccinimide in a polar aprotic solvent such as acetonitrile or tetrahydrofuran for a few hours at low temperature (e.g. -10 – 0 oC).
  • a brominating agent such as N-bromosuccinimide
  • a polar aprotic solvent such as acetonitrile or tetrahydrofuran
  • Intermediate III and carbonyl intermediate IVa (or IVb) can be combined to give intermediate Va (or Vb) through a reductive amination reaction that can be performed in an appropriate solvent such as DCM or THF, in the presence of a Lewis acid such as chloro(triisopropoxy)titanium(IV) or titanium tetraisopropoxide(IV) followed by addition of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence of an organic acid such as acetic acid or trifluoroacetic acid.
  • a Lewis acid such as chloro(triisopropoxy)titanium(IV) or titanium tetraisopropoxide(IV)
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • Intermediate Va can be converted into intermediate VIa (or VIb) by a direct introduction of group R 1 through a metal/palladium catalyzed cross coupling reaction such as Stille coupling, Suzuki coupling or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005).
  • a suitable palladium catalyzed cross coupling for introducing R1 when it is an 2-aminopyrimidin-4- yl is a Stille coupling.
  • a Stille coupling can be performed by reacting intermediate Va (or Vb) with the corresponding organostannane of group R 1 , in the presence of a Pd catalyst such as tetrakistriphenylphosphinepalladium(0), tris(dibenzylideneacetone)dipalladium(0), or PdCl 2 (dppf) 2 , in an organic solvent such as dioxane or THF or DMF, in the presence of a copper(I) salt such as copper(I) thiophene- 2-carboxylate, under heating (90-150oC).
  • Pd catalyst such as tetrakistriphenylphosphinepalladium(0), tris(dibenzylideneacetone)dipalladium(0), or PdCl 2 (dppf) 2
  • organic solvent such as dioxane or THF or DMF
  • a copper(I) salt such as copper(I) thiophene- 2-carboxylate
  • R1 is a 2-aminopyrimidin-4-yl
  • the amino group needs to be masked/protected during the Stille coupling.
  • Said amino group may be suitably protected by one or even two Boc groups and removed when convenient trougthout the synthetic sequence.
  • Removal of PG 1 (when PG 1 is methyl or isopropyl) from intermediate VIa to give the intermediate VIIa may be carried out by hydrolysis, using an inorganic base such as LiOH or NaOH in a mixture of an organic solvent such as THF and/or methanol with water, generally at RT and for a time ranging from 1 h to overnight.
  • R 1 is a N-bis-Boc protected 2-aminopyrimidin-4- yl
  • one Boc group could undergo cleavage; then complete Boc removal could be performed by treatment with a strong acid such as trifluoroacetic acid or concentrated hydrochloric acid.
  • Removal of PG 2 (when PG 2 is Boc) from intermediate VIb to give the intermediate VIIb may be carried out by acidic deprotection.
  • an acidic Boc cleavage may be carried out by means of concentrated hydrochloric acid or trifluoroacetic acid.
  • Reaction between acid intermediate VIIa and amino intermediate VIIIa (or acid VIIIb and amine VIIb) to give a compound of formula (I) may be carried out under suitable amide coupling reaction conditions.
  • acid intermediate VIIa may be reacted in the presence of an activating agent such as TBTU, HATU or COMU, with an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and at temperature generally around RT for a time ranging from a few hours to overnight.
  • An alternative condition for amide coupling may be carried out by reacting intermediate VIIa and VIIIa in the presence of 1-(methylsulfonyl)-1H-benzotriazole as a coupling agent, with an organic base such as TEA, at a temperature up to 150oC for a few hours (for example 4 h).
  • a compound of formula (I) contains in R 2 or R 3 a primary or secondary amine, this amino moiety needs to be masked during the amide coupling step by using suitably protected (generally Boc) intermediates VIIIa or VIIIb.
  • the Boc protecting group can be removed by using similar methods to those described above for intermediates VIb after amide coupling.
  • a compound of formula (I) contains in R2 or R3 a tertiary amine or a tertiary amide
  • such compounds can be obtained by further elaboration of a compound of formula (I) (wherein R 2 or R 3 contain a secondary amine) by a reductive amination reaction or an amidation of the corresponding secondary amine using generally known methods.
  • Compounds of formula (I) can be obtained from intermediate X by a direct introduction of group R 1 in the same way (scheme 1) as that described for transformation of intermediate Va into VIa (or Vb into VIb).
  • R 1 is an 2-aminopyrimidin-4-yl, for synthetic convenience the amino group needs to be protected during the Stille coupling.
  • Said amino group may be suitably protected by one or even two Boc groups and removed by acidic cleavage as already described for intermediates VIIa or VIIb.
  • Intermediate X can be obtained by amide coupling of acid intermediate IXa and amino intermediate VIIIa (or acid VIIIb and amine IXb) using similar conditions to that described above for the reaction of VIIa and intermediate VIIIa (or VIIIb and VIIb).
  • Intermediates IXa and IXb can be obtained from Va and Vb respectively by deprotection of PG 1 and PG 2 according to conditions already reported above for intermediate VIa and VIb.
  • the invention is also directed to a compound of formula Va or Vb, and to its use as intermediate in the preparation of compounds of formula (I) wherein PG 1 and PG 2 are suitable protective groups and all the other variables are defined as for compounds of formula (I) above.
  • PG 1 is a (C 1 -C 4 ) alkyl group, preferably selected from methyl, isopropyl, tert-butyl or ethyl, even more preferably PG1 is methyl.
  • a suitable protective group for intermediate compounds Vb, amino protection via carbamate formation, PG 2 is preferably selected from Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), ethyloxycarbonyl or methoxycarbonyl.
  • the invention is also directed to the use of compounds Va or Vb as an intermediate in the preparation of compounds of formula (I) according to the process as described above.
  • the compounds of the invention are inhibitors of kinase activity, in particular Rho-kinase activity.
  • the invention provides a compound of formula (I) for use as a medicament, preferably for the prevention and /or treatment of pulmonary disease.
  • the invention provides the use of a compound (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disorders associated with ROCK enzyme mechanisms, including immune system disorders and particularly for the treatment of disorders such as pulmonary diseases.
  • the invention provides compounds of formula (I) for use in the prevention and /or treatment of immune system disorders including Graft-versus-host disease (GVHD), and for pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH).
  • GVHD Graft-versus-host disease
  • pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH).
  • the invention provides a method for the prevention and/or treatment of disorders associated with ROCK enzymes mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the disorder is an immune system disorder such as Graft-versus-host disease (GVHD), and/or a respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), Pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH).
  • GVHD Graft-versus-host disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • PH Pulmonary hypertension
  • PAH Pulmonary Arterial Hypertension
  • Preferred is the use of the compounds of the invention for the prevention of the aforesaid disorders.
  • the compounds of the invention may be useful in the treatment of many disorders associated with ROCK enzyme mechanisms.
  • the disorders that can be treated by the compounds of the present invention include glaucoma, inflammatory bowel disease (IBD), immune system disorders including Graft-versus-host disease (GVHD), and pulmonary diseases selected from asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease such as idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).
  • the disorder that can be treated by the compound of the present invention is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease such as idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).
  • the disorder is selected from idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • safety and effective amount in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the particular route of administration chosen.
  • the invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • the present invention is also directed to use of the compounds of the invention and their pharmaceutical compositions for various route of administration Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
  • solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • diluents such as sucrose, mannitol, lactose, starches
  • excipients including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous.
  • liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the compounds of the present invention may be formulated as injectable composition, for example to be injected intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches. Some preferred compounds of the invention exhibit profile suitable for inhalatory route administration.
  • Drugs optimized for inhaled delivery require certain characteristics that allow the compound, when administered to the lung to maintain a sufficient local concentration (lung retention) to exert a pharmacological effect of the desired duration, and non-relevant levels in unwanted compartments (i.e. plasma).
  • lung retention a sufficient local concentration
  • a pharmacological effect of the desired duration i.e. plasma
  • non-relevant levels in unwanted compartments i.e. plasma
  • one or more features of a compounds need to be optimized such as, and not limited to, membrane permeability, dissolution rate and the degree of basicity.
  • permeability is low
  • dissolution rate is sufficiently slow
  • a basic group is present to enhance binding to the phospholipid-rich lung tissue or toallow lysosomial trapping.
  • compounds of the invention show one or more of the features above that are desirable for an inhaled compound.
  • Other preferred compounds of the invention exhibit a profile suitable for the oral route of administration.
  • Drugs optimized for oral delivery require certain characteristics that allow the orally administered compound to be absorbed by the GI (gastrointestinal) tract and to be poorly cleared in order to give a good bioavailability (F%), thus to maintain a sufficient concentration in plasma and target tissues for a time adequate to sustain pharmacological effect.
  • one or more features of the compounds need to be optimized such as, and not limited to, membrane permeabilty and in vivo clearance. In this respect, to attain high oral bioavailability membrane permeability is high and compounds have reduced metabolic hot spots to (optimized in- vitro clearance).
  • compounds of the invention show one or more of the features above for an oral compound.
  • the compounds according to the invention may be administered by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • inhalable powders for administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier usually non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat ⁇ .
  • the invention provides compounds of formula (I) and/or pharmaceutical compositions thereof, for use via inhalatory route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH), preferably in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF).
  • inhalatory route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH), preferably in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF).
  • the invention provides compounds of formula (I) and/or pharmaceutical compositions thereof, for use via oral route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH), preferably in the prevention and /or treatment of pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH).
  • the compounds of the invention regardless of the route of administration, can be administered as the sole active agent or in combination (i.e.
  • sGC stimulator of soluble guanylate cyclase
  • PGI2 prostaciclin analogue PGI2 and agonist of prostacyclin receptors
  • PDE phosphodiesterases
  • human neutrophilic elastase inhibitors compounds inhibiting the signal transduction cascade, such as tyrosine kinase and/or serine/threonine kinase inhibitors
  • antithrombotic agents for example platelet aggregation inhibitors, anticoagulants or profibrinolytic substances
  • active substances for lowering blood pressure for example calcium antagonists, angiotensin II antagonist
  • the compounds of the invention are dosed in combination with phosphodiesterase V such as sildenafil, vardenafil and tadalafil; organic nitrates and NO donors (for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 , and inhaled NO); synthetic prostacyclin analogue PGI2 such as iloprost, treprostinil, epoprostenol and beraprost; agonist of prostacyclin receptors such as selexipag and compounds of WO 2012/007539; stimulators of soluble guanylate cyclase (sGC) like riociguat and tyrosine kinase like imatinib, sorafenib and nilotinib and endothelin antagonist (for example macitentan, bosentan, sitax
  • the compounds of the invention are dosed in combination with beta2-agonists such as salbutamol, salmeterol, and vilanterol, corticosteroids such as fluticasone propionate or furoate, flunisolide, mometasone furoate, rofleponide and ciclesonide, dexametasone, anticholinergic or antimuscarinic agents such as ipratropium bromide, oxytropium bromide, tiotropium bromide, oxybutynin, and combinations thereof.
  • beta2-agonists such as salbutamol, salmeterol, and vilanterol
  • corticosteroids such as fluticasone propionate or furoate, flunisolide, mometasone furoate, rofleponide and ciclesonide
  • dexametasone anticholinergic or antimuscarinic agents
  • anticholinergic or antimuscarinic agents such as ipratropium bromide,
  • the compounds of the invention are dosed in combination with mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs), mucus regulators, mucolytics, expectorant/mucokinetic modulators, peptide mucolytics inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma.
  • mitogen-activated protein kinases P38 MAP kinase
  • IKK2 nuclear factor kappa-B kinase subunit beta
  • NSAIDs non-steroidal anti-inflammatory agents
  • mucus regulators mucolytics
  • expectorant/mucokinetic modulators peptide mucolytics inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma.
  • the invention is also directed to a kit comprising the pharmaceutical compositions of compounds of the invention alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.
  • a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.
  • the dosages of the compounds of the invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.
  • the compounds of formula (I) can be administered for example, at a dosage comprised between 0.001 and 10000 mg/day, preferably between 0.1 and 500 mg/day.
  • a dosage comprised between 0.001 and 500 mg/day preferably between 0.1 and 100 mg/day.
  • a pharmaceutical composition comprising a compound of the invention suitable to be administered by inhalation is in various respirable forms, such as inhalable powders (DPI), propellant-containing metering aerosols (PMDI) or propellant-free inhalable formulations (e.g. UDV).
  • the invention is also directed to a device comprising the pharmaceutical composition comprising a compound according to the invention, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a nebulizer particularly soft mist nebulizer.
  • a compound according to the invention may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a nebulizer particularly soft mist nebulizer.
  • the compounds according to the invention can be administered by inhalation; they may be in some case preferably be administered by the oral route.
  • the compounds of formula (I) are administered by oral route, they are preferably given at a dosage comprised from 0.001 mg to 100 mg per kg body weight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, in single or multiple doses per day.
  • a pharmaceutical composition comprising a compound of the invention suitable to be administered by the oral route can be in various solid or liquid forms, such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders or aqueous and non- aqueous solutions, emulsions, suspensions, syrups, and elixirs formulations.
  • solid or liquid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders or aqueous and non- aqueous solutions, emulsions, suspensions, syrups, and elixirs formulations.
  • Purification by 'chromatography' or 'flash chromatography' refers to purification using the Biotage SPl purification system or equivalent MPLC system using a pre-packed polypropylene column containing unbounded activated silica with irregular particles with average size of 50 ⁇ m and nominal 60 ⁇ porosity.
  • 'NH-silica' and 'C18-silica' are specified, they refer respectively to aminopropyl chain bonded silica and octadecyl carbon chain (C18)-bonded silica.
  • Isolute® SCX-2 cartridge refers to a pre-packed polypropylene column containing a non-end-capped propylsulphonic acid functionalised silica strong cation exchange sorbent.
  • NMR spectra were obtained on a Bruker Avance 400 MHz, 5mm QNP probe H, C, F, P, single Z gradient, two channel instrument running TopSpin 2.1, or on a Bruker Avance III 400 MHz, 5mm BBFO Plus probe, single Z gradient, two channel instrument running TopSpin 3.0, or on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz. Chemical shift are reported as ⁇ values in ppm relative to tetramethylsilane.
  • the compounds were purified using the column and conditions specified and fractions that contained the desired product were concentrated by vacuum centrifugation.
  • the modifier used under basic conditions was diethyl amine (0.1% V/V).
  • Alternate modifiers such as formic acid (0.1% V/V), acetic acid (0.1% V/V), were used as an acidic modifier.
  • MDAP Methods Compounds were purified by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or Gilson preparative HPLC system (322 pump, 155 UV/VIS detector, GX-281 liquid handler) or equivalent system.
  • ACN acetonitrile
  • BINAP (2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene)
  • COMU ((1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate)
  • DCM diichloromethane
  • DIPEA or DIEA N- Ethyldiisopropylamine
  • DMF N,N-Dimethylformamide
  • DMSO Dimethylsulfoxide
  • dppf (1,1′-Ferrocenediyl-bis(diphenylphosphine)
  • EtOH ethanol
  • EtOAc ethyl acetate
  • FA Formmic acid
  • HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid he
  • the reaction was quenched with aqueous saturated NaHCO 3 (500 mL), water (500 mL), EtOAc (1000 mL) and aqueous 5% NaCl (500 mL).
  • the resulting organic and aqueous phases were separated, and the aqueous layer further washed with EtOAc (1000 mL).
  • the combined organic layers were washed with aqueous 5% NaCl (7 x 2000 mL) and concentrated to dryness.
  • the residual solid was treated with a mixture of EtOAc (500 mL) and water (200 mL), placed in a sonic bath for some minutes and acidified with aqueous 10% KHSO 4 (300 mL). The solid that appeared was collected by filtration.
  • the biphasic filtrate was partitioned, and the organic layer washed twice with aqueous 10% KHSO 4 (200 mL each). The combined aqueous layer was washed with EtOAc (3 x 500 mL) and mixed with the previous collected solid. The resulting aqueous mixture was neutralized to pH7 with NaHCO 3 and extracted with EtOAc (3 x 1000 mL). The combined organic phase was washed with saturated aqueous NaCl (500 mL), dried over anhydrous MgSO 4 , and concentrated to give the title compound (27.1 g).
  • the reaction mixture diluted with ethyl acetate, was filtered through a pad of diatomaceous earth.
  • the solution was concentrated in vacuo and the residue was purified by cromatography on a silica gel cartridge eluting with 0-100% ethyl acetate in cyclohexane to give the title product (929 mg).
  • the reaction mixture was diluted with EtOAc and washed with water.
  • the organic layer was passed through a phase separator, loaded onto an SCX-2 cartridge, washed with MeOH and eluted with 2N methanolic ammonia, and the latter was concentrated in vacuo.
  • the residue was purified by flash chromatography on a silica gel cartridge eluting with 0 to 6% 2N methanolic ammonia in DCM, concentrated and freeze-dried to afford the desired product (49 mg).
  • Example 2 to 50 The following examples were prepared from intermediate 1J and the given amine using a method similar to that used for example 1.
  • Example 32-33, 34-35 and 45-47 were prepared as racemic mixture by using the amine indicated in the table and then resolved by chiral SFC according to the methods described below.
  • Step B 3-(Methoxy- 1-amine (Intermediate 6B) To a stirred solution of Intermediate 6A (150 mg, 0.78 mmol) in DCM (3 mL) was added TFA (0.3 mL, 3.9 mmol) and the reaction mixture was stirred at RT for 18 h.
  • Example 51 3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5-methoxypyridin-2-yl)benzamide (Example 51)
  • Intermediate 1J 94 mg, 0.259 mmol
  • 1-(methylsulfonyl)-1H- benzotriazole 204 mg, 1.03 mmol
  • 2-methyltetrahydrofuran 4 mL
  • triethylamine (0.22 mL)
  • 2-amino-5-methoxypyridine 64 mg, 0.517 mmol
  • the reaction was heated to 150°C under microwave irradiation for 3 hours. Further triethylamine (0.11 mL) and 1- (methylsulfonyl)-1H-benzotriazole (105 mg, 0.570 mmol) were added and the reaction was heated to 150°C for a further 4 hours. The reaction was stirred at 175°C under microwave irradiation for a further 2 hours. The reaction mixture was purified using an SCX-2 column, eluting with methanol followed by 2N methanolic ammonia. The relevant fractions were combined and concentrated in vacuo.
  • the resulting residue was dissolved in DCM and purified using flash chromatography on silica gel by eluting with 0-100% DCM in ethyl acetate, followed by 20% methanol in ethyl acetate. The relevant fractions were combined and concentrated in vacuo.
  • the resulting residue was dissolved in 1:1 acetonitrile water and freeze dried.
  • the resulting solid was purified by MDAP (Sunfire C1819x150mm, 10um 5-60% acetonitrile/H 2 O (0.1% FA), 20 mL/min RT) to give the desired product (12.7 mg).
  • Example 52 to 53 The following examples were prepared from intermediate 1J and the given amine using a method similar to that used for example 51.
  • the Boc group was removed after amide coupling using similar reaction conditions to that described in step J for the preparation of intermediate 1J.
  • Example 54 Step A Methyl 3-(((7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2- fluorobenzoate (Intermediate 54A) To a stirred solution of Intermediate 1D (0.40 g, 1.86 mmol), methyl 2-fluoro-3- formylbenzoate (0.58 g, 3.49 mmol) and molecular sieves 4 ⁇ in DCM (9 mL) was added chlorotriisopropoxytitanium(IV) (0.97 mg, 3.72 mmol) and the resulting suspension was allowed to stir at room temperature for 2 h.
  • Methylamine hydrochloride (109 mg, 1.62 mmol) was added and the solution stirred at RT for 1 h. Water was added to the solution and the product was extracted three times with 2-Me-THF. The combined organic phase was dried with Na 2 SO 4 , filtered and concentrated in vacuo. The crude was purified by flash chromatography on a silica gel cartridge eluting with 0-10% MeOH in DCM to give the desired product (205 mg).
  • the reaction mixture was diluted with EtOAc and filtered through diatomaceous earth, washing with EtOAc. The filtrate was washed with water and brine then the organic layers were separated and dried with Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel cartridge, eluting with 0-80% (10% 2M ammonia in MeOH in DCM) in DCM. The relevant fractions were combined and concentrated in vacuo to give the product (269 mg).
  • the reaction mixture was concentrated in vacuo, the residue was diluted with MeOH and was passed down amSCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia.
  • the relevant fractions were evaporated and purified by MDAP (Luna Phenyl-Hexyl 21.2 x 150mm, 10 ⁇ m 5-60% MeOH/H 2 O (0.1% FA), 20mL/min, RT) then purified again by MDAP (Sunfire C1819 x 150mm, 10 ⁇ m 5-95% ACN/H 2 O (0.1% FA), 20mL/min, RT) to give the product (20.1 mg).
  • Example 56 Step A Methyl 3-(((7-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2,3- dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2-fluorobenzoate (Intermediate 56A)
  • Intermediate 56A was prepared using a similar procedure to that used for intermediate 1H by replacing intermediate 1E with intermediate 54A.
  • Example 56 was prepared using a similar procedure to that used for step K of Example 1 by replacing intermediate Intermediate 1J and cyclobutylamine respectively with Intermediate 56C and 4-aminotetrahydropyran.
  • Example 57 to 63 The following examples were made using a similar procedure to that used for step K of Example 1 by replacing intermediate Intermediate 1J and cyclobutylamine respectively with the acid intermediate and amine indicated in the table below.
  • the reaction was stirred at RT under argon for 18 h.
  • the reaction mixture was quenched using 1 M NaOH (20 mL) and the resulting suspension was filtered through diatomaceous earth,washing with water and DCM. The phases of the filtrate were separated, and the organic phase was dried withNa 2 SO 4 , filtered and concentrated in vacuo.
  • the product was purified by flash chromatography on a silica gel cartridge, eluting with 0-50% EtOAc in cyclohexane. The relevant fractions were combined and concentrated in vacuo to give the desired product (487 mg).
  • the reaction mixture was diluted with EtOAc and filtered through Celite ® .
  • the resulting filtrate was washed with water and brine then the organic layers were separated and dried with Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was dissolved in DCM and purified by flash chromatography on a silica gel cartridge, eluting with 0-40% EtOAc in DCM. The relevant fractions were combined and concentrated in vacuo to give the title product (181 mg).
  • reaction mixture was diluted with MeOH and then passed down anSCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia.
  • the relevant fractions were evaporated and further purified by MDAP (Luna Phenyl-Hexyl 21.2 x 150mm, 10 ⁇ m 20- 80% MeOH/H 2 O (0.1% FA), 20mL/min, RT) to give the title product (28 mg).
  • the reaction mixture diluted with MeOH, was passed down an SCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia.
  • the solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel by eluting with 0-10% MeOH in EtOAc. The relevant fractions were combined and concentrated.
  • the residue was purified by MDAP (Luna Phenyl-Hexyl MeOH Acidic 5-60, Luna Phenyl-Hexyl 21.2x150mm, 10 ⁇ m 5-60% MeOH / H 2 O (0.1% FA), 20 mL/min, RT) to give the product (21 mg).
  • the resulting mixture was diluted with water and extracted with Me-THF.
  • the organic layer was dried with Na 2 SO 4 and concentrated in vacuo.
  • the residue was dissolved in water (8 mL), THF (7 mL) and MeOH (3 mL). More lithium hydroxide monohydrate (125 g, 2.98 mmol) was added and the reaction was left to stir at room temperature for a further 3 h.
  • the organic phase was evaporated and the aqueous phase was acidified to pH 2 ⁇ 3 using 1M HCl.
  • the resulting mixture was diluted with water and extracted with Me-THF.
  • the organic layer was dried (with Na2SO4) and concentrated in vacuo to give the desired product (697 mg).
  • the reaction mixture was diluted with ethyl acetate and filtered through a pad of diatomaceous earth. The solution was washed with water and brine and the organic phase was combined, dried with Na 2 SO 4 , filtered and concentrated in vacuo.
  • the resulting crude was dissolved in DCM and methanol and purified using flash chromatography on silica gel by eluting with 0-5% methanol in DCM. The residue was concentrated in vacuo, dissolved in DCM and purified using flash chromatography on silica eluting with 0-5% methanol in DCM. The relevant fractions from both purifications were combined and concentrated in vacuo to give the product (79 mg).
  • ROCK1 and ROCK2 The effectiveness of compounds of the present invention to inhibit Rho kinase activity can be determined in a 10 ⁇ l assay containing 40mM Tris pH7.5, 20mM MgCl 2 0.1mg/mL BSA, 50 ⁇ M DTT and 2.5 ⁇ M peptide substrate (Myelin Basic Protein) using an ADP-Glo kit (Promega). Compounds were dissolved in DMSO such that the final concentration of DMSO was 1% in the assay. All reactions/incubations are performed at 25oC.
  • the compounds according to the invention are at least 5 fold, preferably equal to or more than 10 fold, selective in terms of ROCK2 selectivity vs PKA. Overall the compounds of the invention are more selective than the comparative example C.
  • the compounds are classified in term of selectivity with respect to their ratio of inhibitory activity (Ki) of PKA on ROCK2 isoform according to the following classification criterion: *** : ratio ⁇ 10 ** : 5 ⁇ ratio ⁇ 10 * : ratio ⁇ 5

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Abstract

The invention relates to compounds of formula (I) inhibiting Rho Kinase that are dihydrofuropyridine derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. Particularly the compounds of the invention may be useful in the treatment of many disorders associated with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).

Description

DIHYDROFUROPYRIDINE DERIVATIVES AS RHO- KINASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to novel compounds inhibiting Rho Kinase (hereinafter ROCK Inhibitors); methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
BACKGROUND OF THE INVENTION
The compounds of the invention are inhibitors of the activity or function of the ROCK -I and/or ROCK-II isoforms of the Rho-associated coiled-coil forming protein kinase (ROCK).
Rho-associated coiled-coil forming protein kinase (ROCK) belongs to the AGC (PKA/PKG/PKC) family of serine-threonine kinases. Two human isoforms of ROCK have been described, ROCK-I (also referred to as pl60 ROCK or ROKp or ROCK1) and ROCK-II (ROKa or ROCK2) are approximately 160 kDa proteins containing an N-terminal Ser/Thr kinase domain, followed by a coiled-coil structure, a pleckstrin homology domain, and a cysteine-rich region at the C-terminus (Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446-456).
Both ROCK-II and ROCK-I are expressed in many human and rodent tissues including the heart, pancreas, lung, liver, skeletal muscle, kidney and brain (above Riento and Ridley, 2003). In patients with pulmonary hypertension, ROCK activity is significantly higher in both lung tissues and circulating neutrophils as compared with controls (Duong-Quy S, Bei Y, Liu Z, Dinh-Xuan AT. Role of Rho-kinase and its inhibitors in pulmonary hypertension. Pharmacol Ther. 2013;137(3):352-64). A significant correlation was established between neutrophil ROCK activity and the severity and duration of pulmonary hypertension (Duong-Quy et al., 2013).
There is now substantial evidence that ROCK is involved in many of the pathways that contribute to the pathologies associated with several acute and chronic pulmonary diseases, including asthma, COPD, bronchiectasis and ARDS/ALI. Given the biological effect of ROCK, selective inhibitors have the potential to treat a number of pathological mechanisms in respiratory diseases, such as smooth muscle hyper-reactivity, bronchoconstriction, airway inflammation and airway remodeling, neuromodulation and exacerbations due to respiratory tract viral infection (Fernandes LB, Henry PJ, Goldie RG. Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2007 Oct;l(l):25-33). Indeed the Rho kinase inhibitor Y-27632 causes bronchodilatation and reduces pulmonary eosinophilia trafficking and airways hyperresponsiveness (Gosens, R.; Schaafsma, D.; Nelemans, S. A.; Halayko, A. J. Rhokinase as a drug target for the treatment of airway hyperresponsiveness in asthma. Mini-Rev. Med. Chem. 2006, 6, 339-348). Pulmonary ROCK activation has been demonstrated in humans with idiopathic pulmonary fibrosis (IPF) and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis, thus indicating ROCK inhibitors as potential powerful pharmacological agents to halt progression of pulmonary fibrosis (Jiang, C.; Huang, H.; Liu, J.; Wang, Y.; Lu, Z.; Xu, Z. Fasudil, a rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. Int. J. Mol. Sci. 2012, 13, 8293-8307).
Various compounds have been described in the literature as Rho Kinase Inhibitors. See e.g. W02004/039796 disclosing phenylaminopyrimidine compounds derivatives; W02006/009889 disclosing indazole compound derivatives; W02010/032875 disclosing nicotinamide compounds derivatives; W02009/079008 disclosing pyrazole derivatives; WO2014/118133 disclosing pyrimidine derivatives and, of the same Applicant of the present invention, WO2018/115383 disclosing bicyclic dihydropyrimidine and WO 2018/138293, WO 2019/048479, WO 2019/121223, WO 2019/121233, WO 2019/121406, WO 2019/238628, WO 2020/016129 disclosing tyrosine-amide compounds derivatives and analogues.
The compounds disclosed exhibit substantial structural differences from the compounds of the present invention.
There remains a potential for developing novel and pharmacologically improved ROCK inhibitors in many therapeutic areas.
In view of the number of pathological responses which are mediated by ROCK enzymes, there is a continuing need for inhibitors of such enzymes which can be useful in the treatment of many disorders. The present invention relates to novel compounds differing from the structures disclosed in the art at least for a common new core scaffold. In fact the invention relates to compounds that are characterized by the 2,3-dihydrofuro[3,2-c]pyridine moiety, particularly 2,3-dihydrofuro[3,2-c]pyridin-4- amine, particularly preferably N-(3-(((2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)phenyl)formamide and 3-(((2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)benzamide derivatives, which are inhibitors of ROCK-I and ROCK-II isoforms of the Rho-associated coiled-coil forming protein kinase (ROCK) that have therapeutically desirable characteristics, are particularly promising in the field of respiratory diseases but not excluding other fields such as that of immune system disorders including Graft-versus-host disease (GVHD), and for some pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH) and specifically pulmonary arterial hypertension (PAH). The compounds of the invention may be prepared for administration by any route consistent with their pharmacokinetic properties. The compound of the invention are active as inhibitors of ROCK-I and ROCK-II isoforms, they are potent and have advantageously other improved properties such as selectivity and other in vitro properties indicative for a preferred route of administration. SUMMARY OF THE INVENTION The present invention is directed to a class of compounds, acting as inhibitors of the Rho Kinase (ROCK), of formula (I)
Figure imgf000004_0001
I Wherein the variables X1, X2, X3 and X4, p, R, R1, L, n, R2 and R3, R6 and R7 are as defined in the detailed description of the invention; or pharmaceutically acceptable salts and solvates thereof. In one aspect, the present invention refers to a compound of formula (I) for use as a medicament. In one aspect the present invention provides the use of a compound of the invention for the manufacture of a medicament. In a further aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of any disease associated with ROCK enzyme mechanisms, that is to say characterized by ROCK enzyme aberrant activity and/or wherein an inhibition of activity is desirable and in particular through the selective inhibition of the ROCK enzyme isoforms over other Kinases. In another aspect, the present invention provides a method for prevention and/or treatment of any disease associated with ROCK enzyme mechanisms as above defined, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention. In a Particular aspect the compounds of the invention are used alone or combined with other active ingredients and may be administered for the prevention and/or treatment of immune system disorders including Graft-versus-host disease (GVHD), and for pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH) and specifically pulmonary arterial hypertension (PAH). DETAILED DESCRIPTION OF THE INVENTION Definitions The term “Pharmaceutically acceptable salts” refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups. Cations of inorganic bases which can be suitably used to prepare salts of the invention comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, camphor sulfonic, acetic, oxalic, maleic, fumaric, succinic and citric acids. Many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates” which are a further object of the invention. Polymorphs and crystalline forms of compounds of formula (I), or of pharmaceutically acceptable salts, or solvates thereof are a further object of the invention. The term “Halogen” or “halogen atoms” includes fluorine, chlorine, bromine, and iodine atom ; meaning Fluoro, Chloro, Bromo, Iodo as substituent. The term “(C1-C6)Alkyl” refers to straight-chained or branched alkyl groups wherein the number of carbon atoms is in the range 1 to 6. Particular alkyl groups are for example methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methylbutyl and the like. The expressions “(C1-C6)Haloalkyl” refer to the above defined “(C1-C6)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other. Examples include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl groups. By way of analogy, the terms “(C1-C6)Hydroxyalkyl” and “(C1- C6)aminoalkyl”refer to the above defined “(C1-C6)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more hydroxy (OH) or amino group respectively, examples being hydroxymethyl and aminomethyl and the like. The definition of aminoalkyl encompasses alkyl groups (i.e. “(C1-C6)alkyl” groups) substituted by one or more amino groups (-NR8R9). An example of aminoalkyl is a mono-aminoalkyl group such as R8R9N-(C1-C6)alkyl. The substituents R8 and R9 are defined as R4 and R5 in the above detailed description of the invention. Derived expression such as aminoalkoxyl thus refer to the above define aminoalkyl linked to the rest of the molecule from the alkil side via an ether bridge, e.g. with linear representation -O-(CH2)mNR4R5. The term “(C3-C10)cycloalkyl” likewise “(C3-C8)cycloalkyl” or “(C3- C6)cycloalkyl” refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and polycyclic ring systems such as adamantan-yl. The expression “Aryl” refers to mono, bi- or tri-cyclic carbon ring systems which have 6 to 20, preferably from 6 to 15 ring atoms, wherein at least one ring is aromatic. The expression “heteroaryl” refers to mono-, bi- or tri-cyclic ring systems with 5 to 20, preferably from 5 to 15 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, S or O). Examples of aryl or heteroaryl monocyclic ring systems include, for instance, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl radicals and the like. Examples of aryl or heteroaryl bicyclic ring systems include naphthalenyl, biphenylenyl, purinyl, pteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzoimidazole- yl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothiopheneyl, benzodioxinyl, dihydrobenzodioxinyl, indenyl, dihydro-indenyl, dihydrobenzo[1,4]dioxinyl, benzothiazole-2-yl, dihydrobenzodioxepinyl, benzooxazinyl, 1,2,3,4-tetrahydroisoquinoline-6-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl, 5,6,7,8-tetrahydro-1,7-naphthyridine, 4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl radicals and the like. Examples of aryl or heteroaryl tricyclic ring systems include fluorenyl radicals as well as benzocondensed derivatives of the aforementioned heteroaryl bicyclic ring systems. The derived expression “(C3-C10)heterocycloalkyl” likewise “(C3-C8)heterocycloalkyl” or “(C3-C6)heterocycloalkyl” refers to saturated or partially unsaturated mono, bi- or tri- cycloalkyl groups of the indicated number of carbons, in which at least one ring carbon atom is replaced by at least one heteroatom (e.g. N, NH, S or O) and/or may bear an -oxo (=O) substituent group. Said heterocycloalkyl (i.e. heterocyclic radical or group) is further optionally substituted on the available points in the ring, namely on a carbon atom, or on an heteroatom available for substitution. Examples of heterocycloalkyl are represented by: oxetanyl, tetrahydro-furanyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one-yl, dihydropyrrolyl, 5-oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, octahydrocyclopenta[c]pyrrol-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl; 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl radicals and the like. The term “Aryl(C1-C6)alkyl” refers to an aryl ring linked to a straight-chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. phenylmethyl (i.e. benzyl), phenylethyl or phenylpropyl. Likewise the term “Heteroaryl(C1-C6)alkyl” refers to an heteroaryl ring linked to a straight-chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. furanylmethyl. The term “alkanoyl”, refers to HC(O)- or to alkylcarbonyl groups (e.g. (C1-C6)alkylC(O)-) wherein the group “alkyl” has the meaning above defined. Examples include formyl, acetyl, propanoyl, butanoyl. The term “(C1-C10) alkoxy” or “(C1-C10) alkoxyl”, likewise “(C1-C6) alkoxy” or “(C1-C6) alkoxyl” etc., refers to a straight or branched hydrocarbon of the indicated number of carbons, linked to the rest of the molecule through an oxygen bridge. “(C1-C6)Alkylthio” refers to the above hydrocarbon linked through a sulfur bridge. The derived expression “(C1-C6)haloalkoxy” or “(C1-C6)haloalkoxyl” refers to the above defined haloalkyl, linked through an oxygen bridge. An example of (C1-C6)haloalkoxy is trifluoromethoxy. Likewise derived expression “(C3-C6)heterocycloalkyl-(C1-C6)alkyl” and “(C3-C6)cycloalkyl-(C1-C6)alkyl” refer to the above defined heterocycloalkyl and cycloalkyl groups linked to the rest of the molecule via an alkyl group of the indicated number of carbons, corresponding e.g. to linear formula (C3-C6)heterocycloalkyl- (CH2)m- or (C3-C6)cycloalkyl-(CH2)m- for example piperidin-4-yl-methyl, cyclohexylethyl. The derived expression “(C1-C6)alkoxy-(C1-C6)alkyl” refers to the above defined alkoxy group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example methoxymethyl. Likewise “(C1-C6)haloalkoxy (C1-C6)alkyl” refers to the above defined (C1-C6)haloalkoxy” group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example difluoromethoxypropyl. Derived expression “(C3-C8)heterocycloalkyl-(C1-C6)alkoxyl” or “(C3- C6)heterocycloalkyl-(C1-C6)alkoxyl” and “(C3-C8)cycloalkyl-(C1-C6)alkoxyl” or “(C3- C6)cycloalkyl-(C1-C6)alkoxyl” refer to the above defined heterocycloalkyl and cycloalkyl groups linked to the rest of the molecule via an alkoxyl group as above defined of the indicated number of carbons, corresponding e.g. to linear formula (C3-C8)cycloalkyl - (CH2)mO- (C3-C8)heterocycloalkyl -(CH2)mO- for example piperazin-1-yl-ethoxyl. An oxo moiety is represented by (O) as an alternative to the other common representation, e.g. (=O). Thus, in terms of general formula, the carbonyl group is herein preferably represented as –C(O)– as an alternative to the other common representations such as –CO–, –(CO)– or –C(=O)–. In general the bracketed group is a lateral group, not included into the chain, and brackets are used, when deemed useful, to help disambiguating linear chemical formulas; e.g. the sulfonyl group -SO2- might be also represented as–S(O)2– to disambiguate e.g. with respect to the sulfinic group –S(O)O–. Likewise the group –(CHR3)n-R2 herein is a linear representation of the terminal part of the charachterizing group
Figure imgf000009_0001
found in formula (I) and (Ia). When a numerical index the statement (value) “p is zero” or “p is 0” means that the substituent or group bearing the index p (e.g. (R)p) is absent, that is to say no substituent, other than H when needed, is present. Likewise when the index is attached to a bridging divalent group (e.g. (CH2)n) the statement “n in each occurrence is zero…” or “n is 0” means that the bridging group is absent, that is to say it is a bond. Whenever basic amino or quaternary ammonium groups are present in the compounds of formula (I), physiological acceptable anions, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p- toluenesulfonate, pamoate and naphthalene disulfonate may be present. Likewise, in the presence of acidic groups such as COOH groups, corresponding physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions. Compounds of formula (I) when they contain one or more stereogenic center, may exist as optical stereoisomers. Where the compounds of the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. It is to be understood that all such single enantiomers, diastereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. The absolute configuration (R) or (S) for carbon bearing a stereogenic center is assigned on the basis of Cahn-Ingold-Prelog nomenclature rules based on groups’ priorities. “Single stereoisomer”, “single diastereoisomer” or “single enantiomer”, when reported near the chemical name of a compound indicate that the isomer was isolated as single diastereoisomer or enantiomer (e.g via chiral chromatography) but the absolute configuration at the relevant stereogenic center was not determined/assigned. Atropisomers result from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers (Bringmann G et al, Angew. Chemie Int. Ed. 44 (34), 5384-5427, 2005. doi:10.1002/anie.200462661). Oki defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983). Atropisomers differ from other chiral compounds in that in many cases they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible chemically. Separation of atropisomers is possible by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other. Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other. Racemic forms of compounds of formula (I) as well as the individual atropisomers (substantially free of its corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are included in the scope of the present invention. The invention further concerns the corresponding deuterated derivatives of compounds of formula (I). In the context of the present invention, deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount above its natural abundance. Preferably, the percent of deuterium at that position is at least 90%, more preferably at least 95%, even more preferably 99%. All preferred groups or embodiments described above and herebelow for compounds of formula (I) may be combined among each other and apply as well mutatis mutandis. As above mentioned, the present invention refers to compounds of general formula (I), acting as ROCK inhibitors, to processes for the preparation thereof, pharmaceutical compositions comprising them either alone or in combination with one or more active ingredient, in admixture with one or more pharmaceutically acceptable carriers. In a first aspect the present invention is directed to a class of compounds of formula (I)
Figure imgf000011_0001
I wherein X1, X2, X3 and X4 are all CH or one of X1, X2, X3 and X4 is N and the others are CH; p is zero or an integer from 1 to 4; each R, when present, is in each occurrence independently selected from (C1-C6)alkyl and halogen selected from F, Cl, Br and I; wherein preferably R is F, Cl or methyl; R1 is pyrimidinyl, preferably pyrimidin-4yl, substituted by one or more group selected from -(CH2)mNH2; particularly preferably R1 is 2-aminopyrimidin-4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of -H, halogen, -OH, -(CH2)mNR4R5, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkoxy (C1-C6)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl and (C3-C6)heterocycloalkyl, each of which cycloalkyl, aryl, heteroaryl and heterocycloalkyl is in its turn optionally and independently substituted with one or more groups selected from halogen, -OH, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -(CH2)mNR4R5, -O-(CH2)mNR4R5, alkanoyl, aryl, heteroaryl, cycloalkyl, aryl-(C1-C6)alkyl, heteroaryl-(C1-C6)alkyl, (C3-C8)heterocycloalkyl, preferably (C3-C6)heterocycloalkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, preferably (C3-C6)heterocycloalkyl-(CH2)m-, (C3-C8)cycloalkyl-(C1-C6)alkyl, each of said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is still further optionally substituted by one or more group selected independently from halogen selected from F, Cl, Br and I, preferably F, -OH, (C1-C8)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl; m is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R4 and R5, the same or different, are selected from the group consisting of -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)heterocycloalkyl; R6 and R7 are independently selected from the group consisting of -H, (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof in any proportion and pharmaceutically acceptable salts and solvates thereof. In a preferred embodiment the invention is directed to a compound of formula (I) wherein X1, X3 and X4 are all CH groups and X2 is a CH group or a nitrogen atom; R1 is 2-aminopyrimidin-4-yl; all the other variables being as defined above. Said preferred group of compounds is represented by the formula (Ia)
Figure imgf000013_0001
Ia Particularly preferred are compounds of formula (I) as above defined, wherein X1, X2, X3, X4 are all CH group; each R, when present, is in each occurrence independently selected from F, Cl, Br and I; wherein preferably R is F; R1 is pyrimidinyl substituted by -NH2; particularly preferably R1 is 2- aminopyrimidin-4-yl; L is -C(O)NH-; n is 0 (i.e. R3 is absent); R2 is in each occurrence independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)hydroxyalkyl (C1-C6)haloalkyl, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkoxy (C1-C6)alkyl, all the other variables being as defined above, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof. Said particularly preferred group of compounds is represented by the formula (Ib)
Figure imgf000014_0001
Particularly preferred in this last embodiment is a compound of formula (Ib) wherein R2 is selected from methyl, ethyl, propyl, 2-hydroxy-2-methylpropyl, 3- methoxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-isopropoxypropyl, 3-methoxy-3- methylbutyl, 2-methoxy-2-methylpropyl, 3-fluoropropyl, 2-fluoro-2-methylpropyl, 2,2- difluoropropyl, 3,3-difluoropropyl; all the other variables and substitution being as defined above, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof. In another preferred embodiment the invention is directed to a compound of formula (I) wherein X1, X2, X3 and X4 are all CH; p is zero or an integer from 1 to 4; each R, when present, is halogen in each occurrence independently selected from F, Cl, Br and I, wherein preferably R is F; R1 is pyrimidinyl substituted by -NH2; particularly preferably R1 is 2- aminopyrimidin-4-yl; L is -C(O)NH-; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R3, when present, is H, and R2 is selected from the group consisting of heteroaryl and (C3-C6)heterocycloalkyl, preferably R2 is an heterocycloalkyl, each of which heteroaryl and heterocycloalkyl is in its turn optionally substituted with one or more groups selected from (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, heteroaryl-(C1-C6)alkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl, -O-(CH2)mNR4R5, (C3-C6)heterocycloalkyl m is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R4 and R5, the same or different, are selected from the group consisting of -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, all the other variables being as defined above, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof. Particularly preferred in this last embodiment is a compound wherein R2 is selected from , methoxypyridinyl, ((dimethylamino)ethoxy)pyridin-2-yl, (piperazinyl)pyridinyl, tetrahydrofuranyl, dimethyltetrahydrofuranyl, oxetan-2-yl; all the other variables and substitution being as defined above, or pharmaceutically acceptable salts and solvates thereof. Thus, a group of particularly preferred compounds are
Figure imgf000016_0001
A further preferred group of compounds according to the invention are those of formula (I) wherein X1, X2, X3 and X4 are all CH or X2, is N and the others are CH; p is zero or 1; each R, when present, is F; R1 is 2-aminopyrimidin-4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of -H, (C1-C6)alkyl which is methyl, propyl, isopropyl, tert-butyl, (C1-C6)hydroxyalkyl which is 2-hydroxy-2-methylpropyl, (C1-C6) alkoxy (C1-C6)alkyl which is 3-methoxypropyl, 2-ethoxyethyl, 3- isopropoxypropyl, 3-methoxy-3-methylbutyl, 2-methoxyethyl, 2-methoxy-2- methylpropyl, (C1-C6)haloalkyl which is 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoromethyl, 2-fluoro-2-methylpropyl, 3-fluoropropyl, 2,2-difluoropropyl, 3,3- difluoropropyl, (C1-C6)haloalkoxy (C1-C6)alkyl which is 3-(difluoromethoxy)propyl, (C3-C10)cycloalkyl which is cyclopropyl, cyclobutyl, Heteroaryl which is pyridinyl, and (C3-C6)heterocycloalkyl which is azetidin-3-yl, piperidinyl, morpholinyl, 5- oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, each of which cycloalkyl, heteroaryl and heterocycloalkyl is in its turn optionally and independently substituted with one or more groups selected from halogen which is selected from F, Cl, Br, I, (C1-C6)alkyl which is methyl, tert-butyl, (C1-C6) alkoxy which is methoxy, (C1-C6) alkoxy (C1-C6)alkyl which is methoxymethyl, -O-(CH2)mNR4R5, which is 2-(dimethylamino)ethoxy, wherein m is 2 and R4 and R5 are methyl; (C3-C6)heterocycloalkyl, which is piperazin-1-yl R6 and R7 are -H, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients, either alone or in combination with one or more further active ingredient as detailed below. According to preferred embodiments, the invention provides the compounds listed in the table below and pharmaceutical acceptable salts thereof.
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
The compounds of the invention, including all the compounds hereabove listed, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or by using other known methods, reagents and starting materials. When typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. While the optimum reaction conditions may vary depending on the particular reactants or solvent used, such conditions can be readily determined by those skilled in the art by routine optimization procedures. Thus, processes of preparation described below and reported in the following schemes should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention. In some cases a step is needed in order to mask or protect sensitive or reactive moieties, generally known protective groups (PG) could be employed, in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts). A suitable protective group for intermediates requiring protection of a carboxylic acid (herein reported as PG1) can be C1-C4 esters (PG1: methyl, isopropyl, tert-butyl or ethyl), preferably methyl. A suitable protective group for intermediates requiring the amino group protection (herein reported as PG2) can be carbamates such as tert-butylcarbamate (PG2: tert-butoxycarbonyl or Boc), benzylcarbamate (PG2: Benzyloxycarbonyl or Cbz), ethylcarbamate (PG2: ethoxycarbonyl) or methylcarbamate (PG2: methoxycarbonyl), preferably PG2 is Boc.. The compounds of formula (I), here reported again for clarity, including all the compounds here above listed, can be usually prepared according to the procedures shown in the schemes below. Where a specific detail or step differs from the general schemes it has been detailed in the specific examples, and/or in additional schemes.
Figure imgf000022_0001
I Compounds of formula (I) can contain one or more stereogenic centre. Enantiomerically pure compounds can be prepared according to generally known reactions, e.g. according to the reactions described below, by means of enantiomerically pure starting materials and intermediates. These intermediates may be commercially available or readily produced from commercial sources by those of ordinary skill in the art. In another approach, enantiomerically pure compounds can be prepared from the corresponding racemates by means of chiral chromatography purification. Stereochemically pure compounds may be obtained by chiral separation from a stereoisomers mixture, or (whenever there are two or more stereogenic centres -i.e. chiral center- in compounds of formula (I)) stepwise by chromatographic separation of diastereoisomers followed by further chiral separation into single stereoisomers.
Figure imgf000023_0001
Compounds of formula (I) can be prepared according to scheme 1 starting from comercially available intermediate II or easily obtainable by those skilled in art. Intermediate II can be converted into intermediate III by means of four consecutive steps including 1) chlorination, 2) amination, 3) reduction and 4) bromination. For example, the chlorination step may be carried out by refluxing intermediate II with an appropriate chlorinating agent (neat or in solution with an organic solvent such as DCM or dioxane) such as POCl3 or SOCl2. The amination step can be carried out by introducing a masked ammonia such as benzophenone imine through a Buchwald type palladium catalyzed reaction using, for example, tris(dibenzylideneacetone)dipalladium(0)/BINAP catalytic system followed by hydrolysis of the benzophenone imine by using hydroxylamine to give the corresponding furo[3,2-c]pyridin-4-amine. Alternatively, the amination step can be carried out by introducing 4-methoxybenzylamine by means of SNAr reaction (nucleophilic aromatic substitution) followed by deprotection with a strong acid such as trifluoroacetic acid or methansulphonic acid. Reduction of furo[3,2-c]pyridin-4-amine to give 2,3- dihydrofuro[3,2-c]pyridin-4-amine (step 3) can be carried out, for example, by hydrogenation of a solution of furo[3,2-c]pyridin-4-amine in methanol / acetic acid in the presence of a Pd/C catalyst under high H2 pressure (e.g.10 bar) and at a temperature of 50ºC or higher. Finally, intermediate III can be obtained by means of bromination of 2,3- dihydrofuro[3,2-c]pyridin-4-amine (step 4) by reaction with a brominating agent such as N-bromosuccinimide in a polar aprotic solvent such as acetonitrile or tetrahydrofuran for a few hours at low temperature (e.g. -10 – 0 ºC). Intermediate III and carbonyl intermediate IVa (or IVb) can be combined to give intermediate Va (or Vb) through a reductive amination reaction that can be performed in an appropriate solvent such as DCM or THF, in the presence of a Lewis acid such as chloro(triisopropoxy)titanium(IV) or titanium tetraisopropoxide(IV) followed by addition of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence of an organic acid such as acetic acid or trifluoroacetic acid. Intermediate Va (or Vb) can be converted into intermediate VIa (or VIb) by a direct introduction of group R1 through a metal/palladium catalyzed cross coupling reaction such as Stille coupling, Suzuki coupling or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005). For example a suitable palladium catalyzed cross coupling for introducing R1 when it is an 2-aminopyrimidin-4- yl, is a Stille coupling. A Stille coupling can be performed by reacting intermediate Va (or Vb) with the corresponding organostannane of group R1, in the presence of a Pd catalyst such as tetrakistriphenylphosphinepalladium(0), tris(dibenzylideneacetone)dipalladium(0), or PdCl2(dppf)2, in an organic solvent such as dioxane or THF or DMF, in the presence of a copper(I) salt such as copper(I) thiophene- 2-carboxylate, under heating (90-150ºC). Organostannanes are generally commercially available or may be readily prepared by those skilled in the art starting from corresponding commercially available halides. Experimental procedures for the preparation of organostannane not commercially available are reported in the experimental section. When R1 is a 2-aminopyrimidin-4-yl, for synthetic convenience, the amino group needs to be masked/protected during the Stille coupling. Said amino group may be suitably protected by one or even two Boc groups and removed when convenient trougthout the synthetic sequence. Removal of PG1 (when PG1 is methyl or isopropyl) from intermediate VIa to give the intermediate VIIa may be carried out by hydrolysis, using an inorganic base such as LiOH or NaOH in a mixture of an organic solvent such as THF and/or methanol with water, generally at RT and for a time ranging from 1 h to overnight. In the above mentioned reaction condition, whether R1 is a N-bis-Boc protected 2-aminopyrimidin-4- yl, one Boc group could undergo cleavage; then complete Boc removal could be performed by treatment with a strong acid such as trifluoroacetic acid or concentrated hydrochloric acid. Removal of PG2 (when PG2 is Boc) from intermediate VIb to give the intermediate VIIb may be carried out by acidic deprotection. For example, an acidic Boc cleavage may be carried out by means of concentrated hydrochloric acid or trifluoroacetic acid. With these conditions Boc groups on bis-Boc protected 2-aminopyrimidin-4-yl can also be cleaved. Reaction between acid intermediate VIIa and amino intermediate VIIIa (or acid VIIIb and amine VIIb) to give a compound of formula (I) may be carried out under suitable amide coupling reaction conditions. For example, acid intermediate VIIa may be reacted in the presence of an activating agent such as TBTU, HATU or COMU, with an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and at temperature generally around RT for a time ranging from a few hours to overnight. An alternative condition for amide coupling may be carried out by reacting intermediate VIIa and VIIIa in the presence of 1-(methylsulfonyl)-1H-benzotriazole as a coupling agent, with an organic base such as TEA, at a temperature up to 150ºC for a few hours (for example 4 h). Wherein a compound of formula (I) contains in R2 or R3 a primary or secondary amine, this amino moiety needs to be masked during the amide coupling step by using suitably protected (generally Boc) intermediates VIIIa or VIIIb. The Boc protecting group can be removed by using similar methods to those described above for intermediates VIb after amide coupling. In some cases, wherein a compound of formula (I) contains in R2 or R3 a tertiary amine or a tertiary amide, such compounds can be obtained by further elaboration of a compound of formula (I) (wherein R2 or R3 contain a secondary amine) by a reductive amination reaction or an amidation of the corresponding secondary amine using generally known methods. Compounds of formula (I) can be obtained from intermediate X by a direct introduction of group R1 in the same way (scheme 1) as that described for transformation of intermediate Va into VIa (or Vb into VIb). When R1 is an 2-aminopyrimidin-4-yl, for synthetic convenience the amino group needs to be protected during the Stille coupling. Said amino group may be suitably protected by one or even two Boc groups and removed by acidic cleavage as already described for intermediates VIIa or VIIb. Intermediate X can be obtained by amide coupling of acid intermediate IXa and amino intermediate VIIIa (or acid VIIIb and amine IXb) using similar conditions to that described above for the reaction of VIIa and intermediate VIIIa (or VIIIb and VIIb). Intermediates IXa and IXb can be obtained from Va and Vb respectively by deprotection of PG1 and PG2 according to conditions already reported above for intermediate VIa and VIb. The invention is also directed to a compound of formula Va or Vb, and to its use as intermediate in the preparation of compounds of formula (I) wherein PG1 and PG2 are suitable protective groups and all the other variables are defined as for compounds of formula (I) above. Particularly for intermediate compound Va, carboxylic acid protection via ester formation, PG1 is a (C1-C4) alkyl group, preferably selected from methyl, isopropyl, tert-butyl or ethyl, even more preferably PG1 is methyl. A suitable protective group for intermediate compounds Vb, amino protection via carbamate formation, PG2 is preferably selected from Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), ethyloxycarbonyl or methoxycarbonyl. The invention is also directed to the use of compounds Va or Vb as an intermediate in the preparation of compounds of formula (I) according to the process as described above. As herein described in details, the compounds of the invention are inhibitors of kinase activity, in particular Rho-kinase activity. In one aspect the invention provides a compound of formula (I) for use as a medicament, preferably for the prevention and /or treatment of pulmonary disease. In a further aspect the invention provides the use of a compound (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disorders associated with ROCK enzyme mechanisms, including immune system disorders and particularly for the treatment of disorders such as pulmonary diseases. In particular the invention provides compounds of formula (I) for use in the prevention and /or treatment of immune system disorders including Graft-versus-host disease (GVHD), and for pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH). Moreover the invention provides a method for the prevention and/or treatment of disorders associated with ROCK enzymes mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention. In particular the invention provides methods for the prevention and/or treatment wherein the disorder is an immune system disorder such as Graft-versus-host disease (GVHD), and/or a respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), Pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH). Preferred is the use of the compounds of the invention for the prevention of the aforesaid disorders. Equally preferred is the use of the compounds of the invention for the treatment of the aforesaid disorders. Generally speaking, compounds which are ROCK inhibitors may be useful in the treatment of many disorders associated with ROCK enzyme mechanisms. In one embodiment, the disorders that can be treated by the compounds of the present invention include glaucoma, inflammatory bowel disease (IBD), immune system disorders including Graft-versus-host disease (GVHD), and pulmonary diseases selected from asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease such as idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). In another embodiment, the disorder that can be treated by the compound of the present invention is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease such as idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). In a further embodiment, the disorder is selected from idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). The methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan. The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the particular route of administration chosen. The invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A. The present invention is also directed to use of the compounds of the invention and their pharmaceutical compositions for various route of administration Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous. Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be formulated as injectable composition, for example to be injected intravenously, in the form of an isotonic sterile solution. Other preparations are also possible. Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known. For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches. Some preferred compounds of the invention exhibit profile suitable for inhalatory route administration. Drugs optimized for inhaled delivery require certain characteristics that allow the compound, when administered to the lung to maintain a sufficient local concentration (lung retention) to exert a pharmacological effect of the desired duration, and non-relevant levels in unwanted compartments (i.e. plasma). To attenuate lung absorpion, one or more features of a compounds need to be optimized such as, and not limited to, membrane permeability, dissolution rate and the degree of basicity. In this respect, to attain lung retention, permeability is low, dissolution rate is sufficiently slow, and a basic group is present to enhance binding to the phospholipid-rich lung tissue or toallow lysosomial trapping. In some embodiments, compounds of the invention show one or more of the features above that are desirable for an inhaled compound. Other preferred compounds of the invention exhibit a profile suitable for the oral route of administration. Drugs optimized for oral delivery require certain characteristics that allow the orally administered compound to be absorbed by the GI (gastrointestinal) tract and to be poorly cleared in order to give a good bioavailability (F%), thus to maintain a sufficient concentration in plasma and target tissues for a time adequate to sustain pharmacological effect. To enhance oral bioavalability, one or more features of the compounds need to be optimized such as, and not limited to, membrane permeabilty and in vivo clearance. In this respect, to attain high oral bioavailability membrane permeability is high and compounds have reduced metabolic hot spots to (optimized in- vitro clearance). In some embodiments, compounds of the invention show one or more of the features above for an oral compound. For the treatment of the diseases of the respiratory tract, the compounds according to the invention, as above said, may be administered by inhalation. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir. A diluent or carrier, usually non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention. Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients. The propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat ^. Further preferably the invention provides compounds of formula (I) and/or pharmaceutical compositions thereof, for use via inhalatory route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH), preferably in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF). Further preferably the invention provides compounds of formula (I) and/or pharmaceutical compositions thereof, for use via oral route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH), preferably in the prevention and /or treatment of pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH).The compounds of the invention, regardless of the route of administration, can be administered as the sole active agent or in combination (i.e. as co- therapeutic agents administered in fixed dose combination or in combined therapy of separately formulated active ingredients) with other pharmaceutical active ingredients selected from organic nitrates and NO donors; inhaled NO; stimulator of soluble guanylate cyclase (sGC); prostaciclin analogue PGI2 and agonist of prostacyclin receptors; compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5 inhibitors; human neutrophilic elastase inhibitors; compounds inhibiting the signal transduction cascade, such as tyrosine kinase and/or serine/threonine kinase inhibitors; antithrombotic agents, for example platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; active substances for lowering blood pressure, for example calcium antagonists, angiotensin II antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, aldosterone synthase inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists; neutral endopeptidase inhibitor; osmotic agents; ENaC blockers; anti-inflammatories including corticosteroids and antagonists of chemokine receptors; antihistamine drugs; anti-tussive drugs; antibiotics such as macrolide and DNase drug substance and selective cleavage agents such as recombinant human deoxyribonuclease I (rhDNase); agents that inhibit ALK5 and/or ALK4 phosphorylation of Smad2 and Smad3; tryptophan hydroylase 1 (TPH1) inhibitors and multi-kinase inhibitors, beta2-agonists, corticosteroids, anticholinergic or antimuscarinic agents, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs), mucus regulators, mucolytics, expectorant/mucokinetic modulators, peptide mucolytics, inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma and combinations thereof. In a preferred embodiment, the compounds of the invention are dosed in combination with phosphodiesterase V such as sildenafil, vardenafil and tadalafil; organic nitrates and NO donors (for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 , and inhaled NO); synthetic prostacyclin analogue PGI2 such as iloprost, treprostinil, epoprostenol and beraprost; agonist of prostacyclin receptors such as selexipag and compounds of WO 2012/007539; stimulators of soluble guanylate cyclase (sGC) like riociguat and tyrosine kinase like imatinib, sorafenib and nilotinib and endothelin antagonist (for example macitentan, bosentan, sitaxentan and ambrisentan). In a further embodiment the compounds of the invention are dosed in combination with beta2-agonists such as salbutamol, salmeterol, and vilanterol, corticosteroids such as fluticasone propionate or furoate, flunisolide, mometasone furoate, rofleponide and ciclesonide, dexametasone, anticholinergic or antimuscarinic agents such as ipratropium bromide, oxytropium bromide, tiotropium bromide, oxybutynin, and combinations thereof. In a further embodiment the compounds of the invention are dosed in combination with mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs), mucus regulators, mucolytics, expectorant/mucokinetic modulators, peptide mucolytics inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma. The invention is also directed to a kit comprising the pharmaceutical compositions of compounds of the invention alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer. The dosages of the compounds of the invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound. Advantageously, the compounds of formula (I) can be administered for example, at a dosage comprised between 0.001 and 10000 mg/day, preferably between 0.1 and 500 mg/day. When the compounds of formula (I) are administered by inhalation route, they are preferably given at a dosage comprised between 0.001 and 500 mg/day, preferably between 0.1 and 100 mg/day. A pharmaceutical composition comprising a compound of the invention suitable to be administered by inhalation is in various respirable forms, such as inhalable powders (DPI), propellant-containing metering aerosols (PMDI) or propellant-free inhalable formulations (e.g. UDV). The invention is also directed to a device comprising the pharmaceutical composition comprising a compound according to the invention, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a nebulizer particularly soft mist nebulizer. Although for the treatment of the diseases of the respiratory tract, the compounds according to the invention can be administered by inhalation; they may be in some case preferably be administered by the oral route. When the compounds of formula (I) are administered by oral route, they are preferably given at a dosage comprised from 0.001 mg to 100 mg per kg body weight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, in single or multiple doses per day. A pharmaceutical composition comprising a compound of the invention suitable to be administered by the oral route can be in various solid or liquid forms, such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders or aqueous and non- aqueous solutions, emulsions, suspensions, syrups, and elixirs formulations. The following examples illustrate the invention in more detail. PREPARATION OF INTERMEDIATES AND EXAMPLES General Experimental details Chemical Names of the compounds were generated with Structure To Name Enterprise 10.0 Cambridge Software or latest. Purification by 'chromatography' or 'flash chromatography' refers to purification using the Biotage SPl purification system or equivalent MPLC system using a pre-packed polypropylene column containing unbounded activated silica with irregular particles with average size of 50 µm and nominal 60Å porosity. When 'NH-silica' and 'C18-silica' are specified, they refer respectively to aminopropyl chain bonded silica and octadecyl carbon chain (C18)-bonded silica. Fractions containing the required product (identified by TLC and/or LCMS analysis) were pooled and concentrated in vacuo or freeze-dried. Where an Isolute® SCX-2 cartridge was used, ‘Isolute® SCX-2 cartridge’ refers to a pre-packed polypropylene column containing a non-end-capped propylsulphonic acid functionalised silica strong cation exchange sorbent.
LCMS Methods Method 1
Figure imgf000035_0001
Method 2
Figure imgf000035_0002
Method 3
Figure imgf000036_0001
Method 4
Figure imgf000036_0002
Method 5
Figure imgf000037_0001
Method 6
Figure imgf000037_0002
Method 7
Figure imgf000038_0001
Method 8
Figure imgf000038_0002
Method 9
Figure imgf000039_0001
Method 10 and Method 11
Figure imgf000039_0002
Method 12
Figure imgf000040_0001
Method 13
Figure imgf000040_0002
NMR Methods NMR spectra were obtained on a Bruker Avance 400 MHz, 5mm QNP probe H, C, F, P, single Z gradient, two channel instrument running TopSpin 2.1, or on a Bruker Avance III 400 MHz, 5mm BBFO Plus probe, single Z gradient, two channel instrument running TopSpin 3.0, or on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz. Chemical shift are reported as δ values in ppm relative to tetramethylsilane. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined. SFC Methods Where compounds were purified using Supercritical Fluid Chromatography (SFC) either a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with Stacked Injection Module) or a Waters Thar Investigator semi preparative system (Waters Fluid Delivery Module, 2998 UV/VIS detector, Waters Fraction Collection Module) was used. The compounds were purified using the column and conditions specified and fractions that contained the desired product were concentrated by vacuum centrifugation. The modifier used under basic conditions was diethyl amine (0.1% V/V). Alternate modifiers such as formic acid (0.1% V/V), acetic acid (0.1% V/V), were used as an acidic modifier. MDAP Methods Compounds were purified by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or Gilson preparative HPLC system (322 pump, 155 UV/VIS detector, GX-281 liquid handler) or equivalent system. Collection was triggered by a threshold absorbance value at 260 nm and the presence of target molecular ion as observed under ESI conditions. The fractions that contained the desired product were lyophilized. The specific details of the conditions used, including the column, solvents, gradient and modifier (acidic or basic), are provided for some examples and merely provided for assistance. When specific conditions are not provided, they can be readily optimized by those skilled in the art. In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step name. When reference is made to the use of a “similar” or “analogous” procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions. The stereochemistry of the compounds in the Examples, where indicated, has been assigned on the assumption that absolute configuration at resolved stereogenic centers of starting materials is maintained throughout any subsequent reaction conditions. All solvents and commercial reagents were used as received. Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Abbreviations ACN (acetonitrile), BINAP (2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene), COMU ((1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate), DCM (dichloromethane), DIPEA or DIEA (N- Ethyldiisopropylamine), DMF (N,N-Dimethylformamide), DMSO (Dimethylsulfoxide), dppf (1,1′-Ferrocenediyl-bis(diphenylphosphine)), EtOH (ethanol), EtOAc (ethyl acetate), FA (Formic acid), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide), HPLC (High performance liquid chromatography), LCMS (Liquid chromatography – mass spectrometry), MDAP (Mass-directed auto-purification), MeOH (methanol), Me-THF (2-Methyltetrahydrofuran), MTBE (methyl tert-butyl ether), NMP (N-methylpyrrolidone), NMR (Nuclear magnetic resonance), Rt (Retention time), RT (Room temperature), SCX (Strong cation exchange), STAB (Sodium triacetoxyborohydride), TBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate), TEA (Triethylamine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran). PREPARATION OF INTERMEDIATES AND EXAMPLES Example 1 Step A
Figure imgf000043_0001
4-Chlorofuro[3,2-c]pyridine (Intermediate 1A) A mixture of furo[3,2‐c]pyridin‐4‐ol (70.4 g, 0.52 mol) in phosphoryl trichloride (430 mL) was heated at reflux for 1 h. Phosphoryl trichloride was distilled off, the residue poured into ice/water and neutralized to pH~6 with aqueous saturated NaHCO3. The aqueous phase was extracted twice with DCM, then the organic layer was washed with saturated aqueous NaCl and evaporated to dryness. The crude material was purified by column chromatography on silica gel eluting with EtOAc-hexane to give the title compound (72.8 g). LCMS (Method 10): Rt = 2.71 min, m/z 153.9 [M+H]+ Step B
Figure imgf000043_0002
Furo[3,2-c]pyridin-4-amine (Intermediate 1B) A solution of Intermediate 1A (72.8 g, 0.47 mol) in dry toluene (730 mL) was purged with argon over 20 min, then racemic BINAP (17.72 g, 0.028 mol), tris(dibenzylideneacetone)dipalladium(0) (8.69 g, 0.0095 mol) and potassium tert- butoxide (74.50 g, 0.66 mol) were added. After addition of benzophenone imine (95.5 mL, 0.57 mol), the mixture was heated at 90°C for 1.5 h. The reaction mixture was cooled to RT, diluted with THF and filtered through a pad of diatomaceous earth followed by washing with THF and diethyl ether. The combined filtrate was evaporated and the residue taken into MeOH (260 mL) and added dropwise to a solution of hydroxylamine hydrochloride (98.87 g, 1.42 mol) in MeOH (1200 mL) which had previously been neutralized in an ice bath with NaOH (56.91 g, 1.42 mol). The reaction mixture was stirred at RT for 1 h and evaporated to dryness. The crude material was purified by chromatography on silica by eluting with 10-100% EtOAc in hexane to give a solid that was further purified by trituration and filtration in a mixture of MTBE and DCM. A second purification by chromatography on silica by eluting with 0-10% MeOH in DCM afforded the pure title compound (45.1 g). LCMS (Method 11): Rt = 0.83 min, m/z 135.0 [M+H]+ Step C
Figure imgf000044_0001
2,3-Dihydrofuro[3,2-c]pyridin-4-amine (Internediate 1C) Intermediate 1B (44.1 g, 0.33 mol) was dissolved in MeOH (530 mL) and acetic acid (56.4 mL), then 10% Pd/C (50% wet, 17.74 g) was added and the reaction mixture purged with argon before being hydrogenated at a pressure of 10 bar of H2 at 50°C under vigorous stirring. After 20 h a further half equivalent of 10% Pd/C (50% wet) and further 3 h of hydrogenation were needed in order to achieve full conversion. The reaction mixture was filtered and washed with MeOH. The combined filtrate was evaporated and the residue partitioned between EtOAc (500 mL) and water (500 mL). The aqueous layer was washed with further EtOAc (300 mL), neutralized with solid NaHCO3 and saturated with NaCl. This aqueous mixture was extracted with DCM (8 x 300 mL) and the combined organic layers washed with saturated aqueous NaCl (800 mL), dried over Na2SO4 and evaporated to afford the title compound (24.57 g). LCMS (Method 12): Rt = 0.81 min, m/z 137.1 [M+H]+ Step D
Figure imgf000044_0002
7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-amine (Intermediate 1D) Intermediate 1C (24.57 g, 0.180 mol) was dissolved in ACN (1230 mL) and then a solution of N-bromosuccinimide (35.33 g, 0.198 mol) in ACN (490 mL) was added dropwise over 3 h at -10ºC in darkness. The reaction was quenched with aqueous saturated NaHCO3 (500 mL), water (500 mL), EtOAc (1000 mL) and aqueous 5% NaCl (500 mL). The resulting organic and aqueous phases were separated, and the aqueous layer further washed with EtOAc (1000 mL). The combined organic layers were washed with aqueous 5% NaCl (7 x 2000 mL) and concentrated to dryness. The residual solid was treated with a mixture of EtOAc (500 mL) and water (200 mL), placed in a sonic bath for some minutes and acidified with aqueous 10% KHSO4 (300 mL). The solid that appeared was collected by filtration. The biphasic filtrate was partitioned, and the organic layer washed twice with aqueous 10% KHSO4 (200 mL each). The combined aqueous layer was washed with EtOAc (3 x 500 mL) and mixed with the previous collected solid. The resulting aqueous mixture was neutralized to pH7 with NaHCO3 and extracted with EtOAc (3 x 1000 mL). The combined organic phase was washed with saturated aqueous NaCl (500 mL), dried over anhydrous MgSO4, and concentrated to give the title compound (27.1 g). LCMS (Method 13): Rt = 1.69 min, m/z 215.0/217.0 [M+H]+ Step E
Figure imgf000045_0001
Methyl 3-(((7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)- benzoate (Intermediate 1E) Intermediate 1D (15.6 g, 0.074 mol) and methyl 3-formylbenzoate (18.1g, 0.11 mol) were dissolved in anhydrous DCM (470 mL) with molecular sieves and kept under inert atmosphere. After 10 min, chloro(triisopropoxy)titanium(IV) (35.4 mL, 0.148 mol) was added dropwise and the resulting mixture stirred at RT over 2.5 h. Sodium triacetoxyborohydride (31.4g, 0.148 mol) followed by acetic acid (8.5 mL, 0.148 mol) were added and the mixture stirred at RT overnight. The reaction mixture was quenched with methanol and solvents were evaporated. The residue was dissolved in EtOAc and aqueous saturated NaHCO3 solution. After being stirred for 15 min, the mixture was filtered through a thin pad of diatomaceous earth and washed with EtOAc. The combined filtrate was collected and organic-aqueous phases were separated. The organic layer was dried over Na2SO4 and evaporated. The crude material was purified by chromatography on silica by eluting with 20% - 40% EtOAc in hexane to give the title compound (19.3g). LCMS (Method 9): Rt = 0.85 min, m/z 362.9/364.9 [M+H]+ Step F
Figure imgf000046_0001
tert-Butyl (4-bromopyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (Intermediate 1F) A solution of 4-bromopyrimidin-2-amine (0.5 g, 2.87 mmol), di-tert-butyl dicarbonate (0.63 g, 2.87 mmol), potassium carbonate (0.79 g, 5.75 mmol) and a catalytic amount of DMAP in dioxane (4 mL) was stirred at ambient temperature for 18 h. Di-tert- butyl dicarbonate (0.94 g, 4.3 mmol) and potassium carbonate (1.58 g, 11.5 mmol) were added and the reaction mixture was stirred at 40°C for 4 h. The reaction mixture, diluted with EtOAc, was washed with saturated aqueous NaCl, the organic layer was dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel by eluting with 0-40% EtOAc in cyclohexane, the relevant fractions were combined and concentrated to give the title product (416 mg). LCMS (Method 8): Rt = 3.69 min, m/z 396.0/398.0 [M+Na]+ Step G
Figure imgf000046_0002
tert-Butyl (tert-butoxycarbonyl)(4-(trimethylstannyl)pyrimidin-2-yl)- carbamate (Intermediate 1G) A degassed mixture of Intermediate 1F (310 mg, 0.828 mmol), hexamethylditin (0.19 mL, 0.911 mmol) and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) in THF (4 mL) was stirred at 80 °C for 6 h. The reaction mixture, diluted with EtOAc, was washed with saturated aqueous NaCl, the organic layer was dried with sodium sulphate and concentrated in vacuo. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel by eluting with 0-50% EtOAc in cyclohexane, the relevant fractions were combined and concentrated to give the desired product (240 mg). LCMS (Method 3): Rt = 3.30 min, m/z 458.3-460.3 [M+H]+ Step H
Figure imgf000047_0001
Methyl 3-(((7-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2,3-di- hydrofuro[3,2-c]pyridin-4-yl)amino)methyl)benzoate (Intermediate 1H) A degassed mixture of Intermediate 1E (1 g, 2.75 mmol), Intermediate 1G (1.39 g, 3.03 mmol), tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.138 mmol) and copper(I) thiophene-2-carboxylate (53 mg, 0.275 mmol) in dioxane (15 mL) was heated at 130 °C under microwave irradiation for 1.5 h. The reaction mixture, diluted with ethyl acetate, was filtered through a pad of diatomaceous earth. The solution was concentrated in vacuo and the residue was purified by cromatography on a silica gel cartridge eluting with 0-100% ethyl acetate in cyclohexane to give the title product (929 mg). LCMS (Method 3): Rt = 3.21 min, m/z 578.5 [M+H]+ Step I
Figure imgf000047_0002
3-(((7-(2-((tert-Butoxycarbonyl)amino)pyrimidin-4-yl)-2,3-dihydrofuro[3,2- c]pyridin-4-yl)amino)methyl)benzoic acid (Intermediate 1I) A mixture of Intermediate 1H (929 mg, 1.62 mmol), lithium hydroxide monohydrate (0.075 g, 1.78 mmol) in THF (3 mL), methanol (3 mL) and water (6 mL) was stirred at ambient temperature for 18 h. Further lithium hydroxide monohydrate (0.15 g, 3.56 mmol) was added and the reaction mixture was stirred for a further 5 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The pH of the aqueous phase was adjusted to pH ~6-7 with aqueous 1M HCl. The organic layer was dried with Na2SO4 and evaporated in vacuo to give the title product (750 mg). LCMS (Method 3): Rt = 1.49 min, m/z 464.3 [M+H]+ Step J
Figure imgf000048_0001
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)benzoic acid (Intermediate 1J) A mixture of Intermediate 1I (2 g, 4.32 mmol) in TFA (10 mL) and dichloromethane (40 mL) was stirred at ambient temperature for 2 h. The reaction mixture, diluted with MeOH, was purified by an SCX-2 cartridge by eluting with MeOH and then 2M methanolic ammonia. The ammonia solution was concentrated in vacuo to give the title product (1.5 g). LCMS (Method 4): Rt = 2.15 min, m/z 364.0 [M+H]+ Step K
Figure imgf000048_0002
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-cyclobutylbenzamide (Example 1) A solution of Intermediate 1J (50 mg, 0.138 mmol), cyclobutylamine (13 µL, 0.151 mmol), TBTU (57 mg, 0.179 mmol) and DIPEA (72 µL, 0.413 mmol) in DMF (1.0 mL) was stirred at RT for 66 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was passed through a phase separator, loaded onto an SCX-2 cartridge, washed with MeOH and eluted with 2N methanolic ammonia, and the latter was concentrated in vacuo. The residue was purified by flash chromatography on a silica gel cartridge eluting with 0 to 6% 2N methanolic ammonia in DCM, concentrated and freeze-dried to afford the desired product (49 mg). LCMS (Method 6): Rt = 2.40 min, m/z 417.1 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.58 (d, J=7.5 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.82 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.39-7.35 (m, 1H), 7.18-7.14 (m, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.41 (s, 2H), 4.74 (t, J=8.9 Hz, 2H), 4.67 (d, J=5.8 Hz, 2H), 4.40 (dt, J=8.4, 16.4 Hz, 1H), 3.03 (t, J=8.9 Hz, 2H), 2.24-2.17 (m, 2H), 2.11-2.01 (m, 2H), 1.70-1.61 (m, 2H). Example 2 to 50 The following examples were prepared from intermediate 1J and the given amine using a method similar to that used for example 1. Example 32-33, 34-35 and 45-47 were prepared as racemic mixture by using the amine indicated in the table and then resolved by chiral SFC according to the methods described below.
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0002
The following example were prepared from their racemic mixtures by SFC using the methods described below.
Figure imgf000066_0001
Synthesis of the amine required for the preparation of Example 6. Intermediate 6A Step A
Figure imgf000067_0001
tert-Butyl (3-(methoxy-d3)propyl)carbamate (Intermediate 6A) tert-Butyl (3-hydroxypropyl)carbamate (0.15 mL, 0856 mmol) was added to a stirred mixture of 0.1M NaOH (1 mL) and toluene (1.5 mL). Tetrabutylammonium bromide (138 mg, 0.428 mmol) was added and the reaction mixture was stirred until dissolution had occurred. Iodomethane-d3 (0.11 mL, 1.71 mmol) was added and the reaction mixture was stirred at RT for 48 h. The reaction mixture was partitioned between water (10 mL) and diethyl ether (10 mL). The aqueous layer was extracted with diethyl ether (10 mL), the combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 0-50% EtOAc in cyclohexane. The relevant fractions were evaporated to give the product (150 mg). ¹H NMR (400 MHz, d6-DMSO) δ 6.84 - 6.69 (m, 1H), 3.29 (t, J=6.3 Hz, 2H), 2.94 (q, J=6.6 Hz, 2H), 1.63 - 1.54 (m, 2H), 1.37 (s, 9H). Step B
Figure imgf000067_0002
3-(Methoxy- 1-amine (Intermediate 6B)
Figure imgf000067_0003
To a stirred solution of Intermediate 6A (150 mg, 0.78 mmol) in DCM (3 mL) was added TFA (0.3 mL, 3.9 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water and was passed down an SCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia. The relevant fractions were evaporated to give the desired product. ¹H NMR (400 MHz, d6-DMSO) δ (t, J=6.4 Hz, 2H), 3.17 (s, 2H), 2.56 (t, J=6.8 Hz, 2H), 1.58 - 1.51 (m, 2H). Example 51
Figure imgf000068_0001
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5-methoxypyridin-2-yl)benzamide (Example 51) To a solution of Intermediate 1J (94 mg, 0.259 mmol) and 1-(methylsulfonyl)-1H- benzotriazole (204 mg, 1.03 mmol) dissolved in 2-methyltetrahydrofuran (4 mL) were added triethylamine (0.22 mL) and 2-amino-5-methoxypyridine (64 mg, 0.517 mmol) and the reaction mixture was flushed with argon. The reaction was heated to 150°C under microwave irradiation for 3 hours. Further triethylamine (0.11 mL) and 1- (methylsulfonyl)-1H-benzotriazole (105 mg, 0.570 mmol) were added and the reaction was heated to 150°C for a further 4 hours. The reaction was stirred at 175°C under microwave irradiation for a further 2 hours. The reaction mixture was purified using an SCX-2 column, eluting with methanol followed by 2N methanolic ammonia. The relevant fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM and purified using flash chromatography on silica gel by eluting with 0-100% DCM in ethyl acetate, followed by 20% methanol in ethyl acetate. The relevant fractions were combined and concentrated in vacuo. The resulting residue was dissolved in 1:1 acetonitrile water and freeze dried. The resulting solid was purified by MDAP (Sunfire C1819x150mm, 10um 5-60% acetonitrile/H2O (0.1% FA), 20 mL/min RT) to give the desired product (12.7 mg). LCMS (Method 4): Rt = 2.61 min, m/z 470.0 (M+H)+ 1H NMR (400 MHz, d6-DMSO) δ 10.62 (br s, 1H), 8.69 (br s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.10 (d, J=6.7 Hz, 1H), 8.01 (s, 1H), 7.89 (s, J=7.8 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.49 (dd, J=3.2, 9.0 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.19 (t, J=6.1 Hz, 1H), 7.07 (d, J=5.3, 1H), 6.43 (br s, 2H), 4.70-4.79 (m, 4H), 3.85 (s, 3H), 3.06 (t, J=8.8 Hz, 2H). Example 52 to 53 The following examples were prepared from intermediate 1J and the given amine using a method similar to that used for example 51. For those examples that use an amino heterocycle containing a Boc protected amino moiety, the Boc group was removed after amide coupling using similar reaction conditions to that described in step J for the preparation of intermediate 1J.
Figure imgf000069_0001
Example 54 Step A
Figure imgf000070_0001
Methyl 3-(((7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2- fluorobenzoate (Intermediate 54A) To a stirred solution of Intermediate 1D (0.40 g, 1.86 mmol), methyl 2-fluoro-3- formylbenzoate (0.58 g, 3.49 mmol) and molecular sieves 4Å in DCM (9 mL) was added chlorotriisopropoxytitanium(IV) (0.97 mg, 3.72 mmol) and the resulting suspension was allowed to stir at room temperature for 2 h. Then sodium triacetoxyborohydride (0.79 g, 3.72 mmol) and acetic acid (0.22 g, 0.21 mL, 3.72 mmol) were added and the resulting mixture was allowed to stir at RT for 24 h. The reaction was quenched with 1N NaOH (8 mL), diluted with DCM and filtered through diatomaceous earth. The filtrate was washed with water, dried with Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on a silica gel cartridge eluting with 0-70% EtOAc in DCM gave the desired product (206 mg). LCMS (Method 1): Rt = 1.24 min, m/z 380.9/382.9 [M+H]+ Step B
Figure imgf000070_0002
3-(((7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2- fluorobenzoic acid (Intermediate 54B) A solution of Intermediate 54A (206 mg, 0.54 mmol) and lithium hydroxide monohydrate (68 mg, 1.62 mmol) dissolved in MeOH (2 mL), THF (2 mL) and water (4 mL) was stirred at room temperature for 20 h. The solution was acidified to pH 5-6 using 1N HCl, then resulting mixture was extracted with 2-Me-THF (x4). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (198 mg). LCMS (Method 3): Rt = 1.33 min, m/z 367/369 [M+H]+ Step C
Figure imgf000071_0001
3-(((7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2-fluoro-N- methylbenzamide (Intermediate 54C) A solution of Intermediate 54B (198 mg, 0.54 mmol), TBTU (225 mg, 0.70 mmol) and DIPEA (0.56 mL, 3.24 mmol) in DCM (5 mL) was stirred at RT for 5 min. Methylamine hydrochloride (109 mg, 1.62 mmol) was added and the solution stirred at RT for 1 h. Water was added to the solution and the product was extracted three times with 2-Me-THF. The combined organic phase was dried with Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography on a silica gel cartridge eluting with 0-10% MeOH in DCM to give the desired product (205 mg). LCMS (Method 1): Rt = 0.90 min, m/z 380/382 [M+H]+ Step D
Figure imgf000071_0002
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-methylbenzamide (Example 54) Intermediate 54C (205 mg, 0.54 mmol), Intermediate 1G (272 mg, 0.59 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol) and copper (I) thiophene-2- carboxylate (10 mg, 0.054 mmol) in dioxane (6 mL) was degassed then heated under microwave irradiation at 130°C for 1.5 h. The resulting mixture was diluted with EtOAc and filtered through diatomaceous earth, washed with saturated aqueous NaCl, dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (2 mL) and added TFA (2 mL), the solution stirred at RT for 3 h. The solution was concentrated in vacuo and the residue diluted with MeOH, was passed down on a SCX-2 cartridge eluting with MeOH and then 7N methanolic ammonia. The ammonia solution was concentrated in vacuo and product purified by MDAP (Sunfire C183x50mm, 3µm, 5- 95% ACN / H2O (0.1% FA), 1.7mL/min, RT) to give the title product (26 mg). LCMS (Method 4): Rt = 2.08 min, m/z 395.0 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.28 (br s, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.19 (dd, J=7.2, 7.2 Hz, 1H), 7.14 (t, J=5.8 Hz, 1H), 7.07 (d, J=5.4 Hz, 1H), 6.43 (s, 2H), 4.76 (t, J=8.5 Hz, 2H), 4.71 (d, J=6.4 Hz, 2H), 3.06 (t, J=8.8 Hz, 2H), 2.79 (d, J=4.6 Hz, 3H). Example 55 Step A
Figure imgf000072_0001
3-(((7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2-fluoro-N- (3-methoxypropyl)benzamide (Intermediate 55A) To a stirred solution of Intermediate 54B (290 mg, 0.790 mmol), 3- methoxypropylamine (0.24 mL, 2.37 mmol) and TBTU (330 mg, 1.03 mmol) in DMF (6 mL) was added DIPEA (0.83 mL, 4.74 mmol) and the reaction mixture was stirred at RT overnight. Further amounts of 3-methoxypropylamine (0.08 mL, 0.79 mmol) and TBTU (254 mg, 0.79 mmol) were added and stirring continued for 12 h. The reaction mixture was diluted with EtOAc and washed with water then a 5% aqueous solution of LiCl. The organics were dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on a silica gel cartridge, eluting with 0-60% (10% 2M ammonia in MeOH in DCM) in DCM. The relevant fractions were combined and concentrated in vacuo to give the desired product (211 mg). LCMS (Method 1): Rt = 1.06 min, m/z 438.1/440.1 [M+H]+ Step B
Figure imgf000073_0001
tert-Butyl (tert-butoxycarbonyl)(4-(4-((2-fluoro-3-((3-methoxypropyl)- carbamoyl)benzyl)amino)-2,3-dihydrofuro[3,2-c]pyridin-7-yl)pyrimidin-2-yl)- carbamate (Intermediate 55B) To a degassed solution of Intermediate 55A (211 mg, 0.481 mmol) and Intermediate 1G (243 mg, 0.530 mmol) in dioxane (5 mL) were added copper (I) thiophene-2- carboxylate (9.2 mg, 0.048 mmol) and tetrakis (triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) and the reaction was stirred at 130°C under microwave irradiation for 1.5 h. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth, washing with EtOAc. The filtrate was washed with water and brine then the organic layers were separated and dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel cartridge, eluting with 0-80% (10% 2M ammonia in MeOH in DCM) in DCM. The relevant fractions were combined and concentrated in vacuo to give the product (269 mg). LCMS (Method 1): Rt = 1.28 min, m/z 653.3 [M+H]+ Step C
Figure imgf000074_0001
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(3-methoxypropyl)benzamide (Example 55) To a stirred solution of Intermediate 55B (269 mg, 0.0.247 mmol) in DCM (2.5 mL) was added TFA (2.5 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, the residue was diluted with MeOH and was passed down amSCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia. The relevant fractions were evaporated and purified by MDAP (Luna Phenyl-Hexyl 21.2 x 150mm, 10µm 5-60% MeOH/H2O (0.1% FA), 20mL/min, RT) then purified again by MDAP (Sunfire C1819 x 150mm, 10µm 5-95% ACN/H2O (0.1% FA), 20mL/min, RT) to give the product (20.1 mg). LCMS (Method 4): Rt = 2.33 min, m/z 453.0 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.35 (t, J=5.0 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.21 - 7.12 (m, 2H), 7.07 (d, J=5.3 Hz, 1H), 6.43 (s, 2H), 4.76 (t, J=8.9 Hz, 2H), 4.71 (d, J=5.9 Hz, 2H), 3.40 (t, J=6.4 Hz, 2H), 3.32 - 3.28 (m, 2H), 3.26 (s, 3H), 3.07 (t, J=8.9 Hz, 2H), 1.80 - 1.72 (m, 2H). Example 56 Step A
Figure imgf000074_0002
Methyl 3-(((7-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2,3- dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2-fluorobenzoate (Intermediate 56A) Intermediate 56A was prepared using a similar procedure to that used for intermediate 1H by replacing intermediate 1E with intermediate 54A. LCMS (Method 1): Rt = 1.49 min, m/z 596.1 [M+H]+ Step B
Figure imgf000075_0001
3-(((7-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2,3- dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-2-fluorobenzoic acid (Intermediate 56B) Intermediate 56B was prepared using a similar procedure to that used for intermediate 1I by replacing intermediate 1H with intermediate 56A. LCMS (Method 1): Rt = 1.32 min, m/z 582.0 [M+H]+ Step C
Figure imgf000075_0002
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluorobenzoic acid (Intermediate 56C) Intermediate 56C was prepared using a similar procedure to that used for intermediate 1J by replacing intermediate 1I with intermediate 56B. LCMS (Method 1): Rt = 0.78 min, m/z 382.0 [M+H]+ Step D
Figure imgf000076_0001
3-(((7-(2-Aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide (Example 56) Example 56 was prepared using a similar procedure to that used for step K of Example 1 by replacing intermediate Intermediate 1J and cyclobutylamine respectively with Intermediate 56C and 4-aminotetrahydropyran. LCMS (Method 4): Rt = 2.31 min, m/z 465.4 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.34 (d, J=7.5 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.20 - 7.13 (m, 2H), 7.07 (d, J=5.3 Hz, 1H), 6.42 (s, 2H), 4.77 (t, J=8.9 Hz, 2H), 4.71 (d, J=5.7 Hz, 2H), 4.05 - 3.95 (m, 1H), 3.90 - 3.85 (m, 2H), 3.44 - 3.37 (m, 2H), 3.07 (t, J=8.5 Hz, 2H), 1.81 - 1.76 (m, 2H), 1.60 - 1.49 (m, 2H). Example 57 to 63 Intermediate 57A to 63A The following intermediates were prepared similarly to Intermediate 54A from Intermediate 1D and the aldehyde indicated.
Figure imgf000077_0001
Intermediate 57B to 63B The following intermediates were prepared using a similar procedure to that used for intermediate 1H by replacing intermediate 1E with indicated starting material.
Figure imgf000078_0001
Intermediate 57C to 63C The following intermediates were prepared using a similar procedure to that used for intermediate 1I by replacing intermediate 1H with indicated starting material.
Figure imgf000079_0001
Figure imgf000080_0002
Intermediate 57D to 63D The following intermediates were prepared using a similar procedure to that used for intermediate 1J by replacing intermediate 1I with indicated starting material.
Figure imgf000080_0001
Figure imgf000081_0002
Example 57 to 63 The following examples were made using a similar procedure to that used for step K of Example 1 by replacing intermediate Intermediate 1J and cyclobutylamine respectively with the acid intermediate and amine indicated in the table below.
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0002
Example 64 Step A
Figure imgf000083_0001
tert-Butyl (3-(((7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)- phenyl)carbamate (Intermediate 64A) To a solution of Intermediate 1D (300 mg, 1.40 mmol) and tert-butyl (3- formylphenyl)carbamate (463 mg, 2.09 mmol) dissolved in DCM (10 mL) was added molecular sieves (4 Å), chlorotriisopropoxytitanium(IV) (0.67 mL, 2.79 mmol) was added and the mixture was stirred for 10 mins before the addition of sodium triacethoxyborohydride (591 mg, 2.79 mmol) and acetic acid (0.16 mL, 2.79 mmol). The reaction was stirred at RT under argon for 18 h. The reaction mixture was quenched using 1 M NaOH (20 mL) and the resulting suspension was filtered through diatomaceous earth,washing with water and DCM. The phases of the filtrate were separated, and the organic phase was dried withNa2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on a silica gel cartridge, eluting with 0-50% EtOAc in cyclohexane. The relevant fractions were combined and concentrated in vacuo to give the desired product (487 mg). LCMS (Method 2): Rt = 1.64 min, m/z 420.3/422.3 [M+H]+ Step B
Figure imgf000084_0001
tert-Butyl (tert-butoxycarbonyl)(4-(4-((3-((tert-butoxycarbonyl)amino)- benzyl)amino)-2,3-dihydrofuro[3,2-c]pyridin-7-yl)pyrimidin-2-yl)carbamate (Intermediate 64B) To a degassed solution of Intermediate 64A (350 mg, 0.833 mmol), Intermediate 1G (420 mg, 0.916 mmol) and copper (I) thiophene-2-carboxylate (16 mg, 0.0833 mmol) dissolved in dioxane (10 mL) was added tetrakis (triphenylphosphine)palladium(0) (48 mg, 0.0416 mmol) and the reaction was stirred at 130°C under microwave irradiation for 1.5 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. The resulting filtrate was washed with water and brine then the organic layers were separated and dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCM and purified by flash chromatography on a silica gel cartridge, eluting with 0-40% EtOAc in DCM. The relevant fractions were combined and concentrated in vacuo to give the title product (181 mg). LCMS (Method 2): Rt = 1.78 min, m/z 635.6 [M+H]+ Step C
Figure imgf000085_0001
N-(3-Aminobenzyl)-7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2- c]pyridin-4-amine (Intermediate 64C) To a solution of Intermediate 64B (181 mg, 0.285 mmol) in DCM (8 mL) was added TFA (0.87 mL, 11.41 mmol) and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the resulting material was dissolved in MeOH and applied to an SCX-2 column, eluting with MeOH then methanolic ammonia. The relevant fractions were combined and concentrated in vacuo to afford the title compound (95 mg). LCMS (Method 2): Rt = 1.08 min, m/z 335.3 [M+H]+ Step D
Figure imgf000085_0002
N-(3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)phenyl)-4-methoxybutanamide (Example 64) To a stirred solution of Intermediate 64C (56 mg, 0.167 mmol), 4-methoxybutanoic acid (22 mg, 0.184 mmol) and TBTU (70mg, 0.184 mmol) in DMF (1.5 mL) was added DIPEA (0.088 mL, 0.502 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with MeOH and then passed down anSCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia. The relevant fractions were evaporated and further purified by MDAP (Luna Phenyl-Hexyl 21.2 x 150mm, 10µm 20- 80% MeOH/H2O (0.1% FA), 20mL/min, RT) to give the title product (28 mg). LCMS (Method 4): Rt = 2.33 min, m/z 435.0 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 9.85 (s, 1H), 8.68 (s, 1H), 8.2, (s, 0.3 H), 8.16 (d, J=5.3 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.22 (t, J=7.8 Hz, 1H), 7.12 (t, J=6.1 Hz, 1H), 7.07 (d, J=5.3 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.42 (s, 2H), 4.75 (t, J=8.9 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 3.23 (s, 3H), 3.04 (t, J=8.9 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.84 - 1.76 (m, 2H). Example A (comparative) Scheme
Figure imgf000086_0001
3-(((7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)benzoic acid (Intermediate AA) A solution of Intermediate 1E (100 mg, 0.27 mmol), lithium hydroxide monohydrate (0.035 g, 0.83 mmol) in THF (1 mL), MeOH (1 mL) and water (2 mL) was stirred at ambient temperature for 1.5 h. The resulting mixture was diluted with water and extracted with EtOAc. The pH of the aqueous phase was adjusted to pH ~2-3 with aqueous 1M HCl. The organic layer was dried over sodium sulphate and evaporated in vacuo to give the title product (89 mg). LCMS (Method 1): Rt = 0.81 min, m/z 348.9/350.9 [M+H]+ Step B
Figure imgf000087_0001
3-(((7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)-N- methylbenzamide (Intermediate AB) A mixture of Intermediate AA (40 mg, 0.12 mmol), methylamine hydrochloride (23 mg, 0.35 mmol), TBTU (150 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) in DCM (4 mL) was stirred at ambient temperature for 18 h. The resulting mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue, diluted with methanol, was passed down an SCX-2 cartridge eluting with methanol and then 2M methanolic ammonia. The relevant fractions were poole d and concentrated to dryness to give the title product (29 mg). LCMS (Method 1): Rt = 0.73 min, m/z 362.0/364.0 [M+H]+ Step C
Figure imgf000087_0002
N-Methyl-3-(((7-(pyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)benzamide (Example A) A degassed mixture of Intermediate AB (100 mg, 0.28 mmol), 4- (tributylstannyl)pyrimidine (110 mg, 0.304 mmol), tetrakis(triphenylphosphine)- palladium(0) (16 mg, 0.014 mmol) and copper(I) thiophene-2-carboxylate (5.3 mg, 0.028 mmol) in dioxane (3 mL) was heated at 150 °C under microwave irradiation for 1 h. The reaction mixture, diluted with MeOH, was passed down an SCX-2 cartridge eluting with MeOH and then 2M methanolic ammonia. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel by eluting with 0-10% MeOH in EtOAc. The relevant fractions were combined and concentrated. The residue was purified by MDAP (Luna Phenyl-Hexyl MeOH Acidic 5-60, Luna Phenyl-Hexyl 21.2x150mm, 10µm 5-60% MeOH / H2O (0.1% FA), 20 mL/min, RT) to give the product (21 mg). LCMS (Method 4): Rt = 2.18 min, m/z 362.2 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ d 9.08 (d, J=1.1 Hz, 1H), 8.80 (s, 1H), 8.69 (d, J=5.5 Hz, 1H), 8.46-8.37 (m, 1H), 7.90 (dd, J=1.4, 5.5 Hz, 1H), 7.83 (s, 1H), 7.70-7.67 (m, 1H), 7.50-7.47 (m, 1H), 7.42-7.33 (m, 2H), 4.81 (t, J=9.0 Hz, 2H), 4.72 (d, J=6.0 Hz, 2H), 3.09 (t, J=9.0 Hz, 2H), 2.78 (d, J=4.6 Hz, 3H). Example B Scheme
Figure imgf000088_0001
2,3-Dihydrofuro[2,3-c]pyridin-7-amine (Intermediate BA) Intermediate BA was prepared using a similar procedure to that described for Intermediate 1C in Step C by replacing Intermediate 1B with furo[2,3-c]pyridin-7-amine. LCMS (Method 10): Rt = 0.75 min, m/z 137.1 [M+H]+ Step B Br N O NH2 4-Bromo-2,3-dihydrofuro[2,3-c]pyridin-7-amine (Intermediate BB) Intermediate BB was prepared similarly to Intermediate 1D by replacing Intermediate 1C of step C with Intermediate BA. LCMS (Method 12): Rt = 1.72 min, m/z 214.8 an 216.8 [M+H]+
Figure imgf000089_0001
Methyl 3-(((4-bromo-2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino)methyl)- benzoate (Intermediate BC) A solution of Intermediate BB (500 mg, 2.33 mmol), methyl 3-formylbenzoate (573 mg, 3.49 mmol) and chlorotriisopropoxytitanium(IV) (1212 mg, 4.65 mmol) dissolved in DCM (15 mL) was stirred at room temperature for 18 h with molecular sieves. To this solution, acetic acid (0.27 mL) and sodium triacetoxyborohydride (1478 mg, 6.98 mmol) were added and the reaction was left to stir at room temperature for 48 h. The reaction mixture was quenched with 1N NaOH (120 mL), filtered through a pad of diatomaceous earth, and washed with DCM. The organic phase was washed with water, dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel by eluting with 0-75% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated in vacuo to give the desired product (718 mg). LCMS (Method 3): Rt = 2.90 min, m/z 363.2/365.2 [M+H]+ Step D
Figure imgf000090_0001
3-(((4-Bromo-2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino)methyl)benzoic acid (Intermediate BD) A solution of Intermediate BC (720 mg, 1.98 mmol) and lithium hydroxide monohydrate (250 mg, 5.95 mmol) dissolved in MeOH (3 mL), THF (3 mL) and water (6 mL) was stirred at room temperature for 6 h. The organic phase was evaporated and the aqueous phase was acidified to pH 2~3 using 1M HCl. The resulting mixture was diluted with water and extracted with Me-THF. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was dissolved in water (8 mL), THF (7 mL) and MeOH (3 mL). More lithium hydroxide monohydrate (125 g, 2.98 mmol) was added and the reaction was left to stir at room temperature for a further 3 h. The organic phase was evaporated and the aqueous phase was acidified to pH 2~3 using 1M HCl. The resulting mixture was diluted with water and extracted with Me-THF. The organic layer was dried (with Na2SO4) and concentrated in vacuo to give the desired product (697 mg). LCMS (Method 2): Rt = 0.92 min, m/z 349.2/351.2 [M+H]+ Step E
Figure imgf000090_0002
3-(((4-Bromo-2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino)methyl)-N- methylbenzamide (Intermediate BE) To a solution of Intermediate BD (250 mg, 0.716 mmol) and TBTU (300 mg, 0.931 mmol) dissolved in DCM (5 mL) were added DIPEA (075 mL) and methylamine hydrochloride (150 mg, 2.15 mmol) and the reaction mixture was left to stir at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried with Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in MeOH and passed through an SCX column eluting with MeOH followed by methanolic ammonia (2M). The relevant fractions were combined and concentrated in vacuo to give the desired product. LCMS (Method 2): Rt = 1.32 min, m/z 362.3/364.2 [M+H]+ Step F
Figure imgf000091_0001
tert-Butyl (tert-butoxycarbonyl)(4-(7-((3-(methylcarbamoyl)benzyl)amino)- 2,3-dihydrofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl)carbamate (Intermediate BF) To a degassed solution of Intermediate BE (122 mg, 0.338 mmol), tetrakis (triphenylphosphine)palladium(0) (20 mg, 0.0169 mmol), copper(I) thiophene-2- carboxylate (6.4 mg, 0.0338 mmol) dissolved in dioxane (3 mL) was added Intermediate 1G (170 mg, 0.371 mmol) and the reaction was stirred at 130°C under microwave irradiation for 1.5 h. The reaction mixture was diluted with ethyl acetate and filtered through a pad of diatomaceous earth. The solution was washed with water and brine and the organic phase was combined, dried with Na2SO4, filtered and concentrated in vacuo. The resulting crude was dissolved in DCM and methanol and purified using flash chromatography on silica gel by eluting with 0-5% methanol in DCM. The residue was concentrated in vacuo, dissolved in DCM and purified using flash chromatography on silica eluting with 0-5% methanol in DCM. The relevant fractions from both purifications were combined and concentrated in vacuo to give the product (79 mg). LCMS (Method 1): Rt = 1.45 min, m/z 577.1 [M+H]+ Step G
Figure imgf000092_0001
3-(((4-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[2,3-c]pyridin-7- yl)amino)methyl)-N-methylbenzamide (Example B) To a solution of Intermediate BF (79 mg,0.137 mmol) dissolved in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 18 h. The reaction mixture was passed down an SCX-2 column eluting with methanol followed by 2M methanolic ammonia. The relevant fractions were combined, concentrated in vacuo, and the residue was purified by MDAP (Luna Phenyl-Hexyl 21.2x150mm, 10µm 5-60% MeOH/H2O (0.1% FA), 20 mL/min, RT) to give the desired product (33.8 mg). LCMS (Method 4): Rt = 3.21 min, m/z 377.0 [M+H]+ 1H NMR (400 MHz, d6-DMSO) δ 8.40 (m, 1H), 8.16-8.20 (m, 2H), 7.81 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.10 (t, J=6.4 Hz, 1H), 6.92 (d, J=5.3 Hz, 1H), 6.48 (br s, 2H), 4.61-4.68 (m, 4H), 3.68 (t, J=8.8 Hz, 2H), 2.78 (d, J=4.6 Hz, 3H).
Example C Scheme
Figure imgf000093_0002
N-Benzyl-7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-amine (Intermediate CA) Intermediate CA was prepared similarly to Intermediate BC by replacing methyl 3- formylbenzoate with benzaldehyde. LCMS (Method 2): Rt = 1.57 min, 303.0-305.0 m/z [M+H]+ Step B
Figure imgf000093_0001
tert-Butyl (4-(4-(benzylamino)-2,3-dihydrofuro[3,2-c]pyridin-7-yl)pyrimidin- 2-yl)(tert-butoxycarbonyl)carbamate (Intermediate CB) Intermediate CB was prepared similarly to Intermediate BF by replacing Intermediate BE with Intermediate CA. LCMS (Method 2): Rt = 1.73 min, m/z 520.4 [M+H]+ Step C
Figure imgf000094_0001
7-(2-Aminopyrimidin-4-yl)-N-benzyl-2,3-dihydrofuro[3,2-c]pyridin-4-amine Example C was prepared similarly to Example B by replacing Intermediate BF of step G with Intermediate CB. LCMS (Method 4): Rt = 2.5 min, m/z 320 [M+H]+ ¹H NMR (400 MHz, d6-DMSO) δ 8.68 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.36 - 7.28 (m, 4H), 7.25 - 7.20 (m, 1H), 7.13 (t, J=5.5 Hz, 1H), 7.07 (d, J=5.0 Hz, 1H), 6.41 (s, 2H), 4.75 (t, J=9.0 Hz, 2H), 4.66 (d, J=6.0 Hz, 2H), 3.04 (t, J=8.9 Hz, 2H). PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION. In vitro inhibitory activity assay description ROCK1 and ROCK2 The effectiveness of compounds of the present invention to inhibit Rho kinase activity can be determined in a 10µl assay containing 40mM Tris pH7.5, 20mM MgCl2 0.1mg/mL BSA, 50µM DTT and 2.5µM peptide substrate (Myelin Basic Protein) using an ADP-Glo kit (Promega). Compounds were dissolved in DMSO such that the final concentration of DMSO was 1% in the assay. All reactions/incubations are performed at 25oC. Compound (2ul) and either Rho kinase 1 or 2 (4µl) were mixed and incubated for 30 mins. Reactions were initiated by addition of ATP (4µl) such that the final concentration of ATP in the assay was 200µM. After a 1 hour incubation 10µl of ADP- Glo Reagent was added and after a further 1 hour incubation 20ul of Kinase Detection Buffer was added and the mixture incubated for a further 45 minutes. The luminescent signal was measured on a luminometer. Controls consisted of assay wells that did not contain compound with background determined using assay wells with no enzyme added. Compounds were tested in dose-response format and the inhibition of kinase activity was calculated at each concentration of compound. To determine the IC50 (concentration of compound required to inhibit 50% of the enzyme activity) data were fit to a plot of % inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope and fixing the maximum to 100% and the minimum to 0%. To determine the Ki values the Cheng-Prusoff equation was utilized (Ki=IC50/(1+[S]/Km). Compounds according to the invention showed Ki values lower than 500 nM on both isoforms. The results for individual compounds are provided below in following table and are expressed as range of activity. In vitro inhibitory activity assay description for PKA The effectiveness of compounds of the present invention to inhibit PKA activity can be determined in a 10µl assay containing 40mM Tris pH7.5, 20mM MgCl20.1mg/ml BSA, 50µM DTT and 260µM peptide substrate (kemptide) using an ADP-Glo kit (Promega). Compounds were dissolved in DMSO such that the final concentration of DMSO was 1% in the assay. All reactions/incubations are performed at 25oC. Compound and PKA enzyme (6µl) were mixed and incubated for 30 mins. Reactions were initiated by addition of ATP (4µl) such that the final concentration of ATP in the assay was 10µM. After a 30 minute incubation 10µl of ADP-Glo Reagent was added and after a further 1 hour incubation 20µl of Kinase Detection Buffer was added and the mixture incubated for a further 45 minutes. The luminescent signal was measured on a luminometer. Controls consisted of assay wells that did not contain compound with background determined using assay wells with no enzyme added. Compounds were tested in dose- response format and the inhibition of kinase activity was calculated at each concentration of compound. To determine the IC50 (concentration of compound required to inhibit 50% of the enzyme activity) data were fit to a plot of % inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope and fixing the maximum to 100% and the minimum to 0%. To determine the Ki values the Cheng-Prusoff equation was utilized (Ki=IC50/(1+[S]/Km). In vitro inhibitory activities for PKA were reported as selectivity ratio vs. ROCK- 2. Selectivity ratio PKA/ROCK2 was calculated by dividing the Ki value for PKA by Ki value of ROCK2 and reported in the following table. Table 1
Figure imgf000096_0001
Figure imgf000097_0001
wherein the compounds are classified in term of potency with respect to their inhibitory activity on ROCK1 and ROCK2 isoforms according to the following classification criterion: + + + : Ki ≤ 3 nM + + : 3 < Ki ≤ 30 nM + : Ki > 30 nM The Compounds according to the invention showed advantageously Ki values equal to or lower than 30 nM , preferably even equal to or lower that 3 nM, at least on ROCK2; further preferably equal to or lower than 30 nM, preferably even equal to or lower that 3 nM on both isoforms. The compounds according to the invention are more potent than the comparative example A and B. Moreover, preferred compounds according to the invention exhibit marked selectivity versus PKA. The compounds according to the invention are at least 5 fold, preferably equal to or more than 10 fold, selective in terms of ROCK2 selectivity vs PKA. Overall the compounds of the invention are more selective than the comparative example C. In the table the compounds are classified in term of selectivity with respect to their ratio of inhibitory activity (Ki) of PKA on ROCK2 isoform according to the following classification criterion: *** : ratio ≥ 10 ** : 5 ≤ ratio < 10 * : ratio < 5

Claims

CLAIMS 1. A compound of formula (I)
Figure imgf000099_0001
I wherein X1, X2, X3 and X4 are all CH or one of X1, X2, X3 and X4 is N and the others are CH; p is zero or an integer from 1 to 4; each R, when present, is in each occurrence independently selected from (C1-C6)alkyl and halogen selected from F, Cl, Br and I; wherein preferably R is F, Cl or methyl; R1 is pyrimidinyl, preferably pyrimidin-4yl, substituted by one or more group selected from -(CH2)mNH2; particularly preferably R1 is 2-aminopyrimidin- 4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of -H, halogen, -OH, -(CH2)mNR4R5, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkoxy (C1-C6)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl and (C3-C6)heterocycloalkyl, each of which cycloalkyl, aryl, heteroaryl and heterocycloalkyl is in its turn optionally and independently substituted with one or more groups selected from halogen, -OH, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -(CH2)mNR4R5, -O-(CH2)mNR4R5, alkanoyl, aryl, heteroaryl, cycloalkyl, aryl-(C1-C6)alkyl, heteroaryl-(C1-C6)alkyl , (C3-C8)heterocycloalkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl, each of said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is still further optionally substituted by one or more group selected independently from halogen selected from F, Cl, Br and I, preferably F, -OH, (C1-C8)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, m is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R4 and R5, the same or different, are selected from the group consisting of -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)heterocycloalkyl; R6 and R7 are independently selected from the group consisting of -H, (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof in any proportion and pharmaceutically acceptable salts and solvates thereof. 2. A compound according to Claim 1, wherein X1, X3 and X4 are all CH groups and X2 is a CH group or a nitrogen atom; R1 is 2-aminopyrimidin-4-yl; all the other variables being as defined in claim 1. 3. A compound according to Claim 1, wherein X1 , X2, X3 , X4 are all CH group; each R, when present, is in each occurrence independently selected from F, Cl, Br and I; R1 is pyrimidinyl substituted by -NH2; L is -C(O)NH-; n is 0; R2 is selected from the group consisting of (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy (C1-C6)alkyl, (C1-C6)haloalkoxy (C1-C6)alkyl, all the other variables being as defined in claim 1, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or or pharmaceutically acceptable salts and solvates thereof. 4. A compound according to Claim 3, wherein R2 is selected from methyl, ethyl, propyl, 2-hydroxy-2-methylpropyl, 3- methoxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-isopropoxypropyl, 3-methoxy- 3-methylbutyl, 2-methoxy-2-methylpropyl, 3-fluoropropyl, 2-fluoro-2- methylpropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof 5. A compound according to Claim 1, wherein X1, X2, X3 and X4 are all CH; p is zero or an integer from 1 to 4; each R, when present, is halogen in each occurrence independently selected from F, Cl, Br and I, wherein preferably R is F; R1 is pyrimidinyl substituted by -NH2; particularly preferably R1 is 2- aminopyrimidin-4-yl; L is -C(O)NH-; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R3, when present, is H, and R2 is (C3-C6)heterocycloalkyl, which is in its turn optionally substituted with one or more groups selected from (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6)alkyl, heteroaryl-(C1-C6)alkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl, -O-(CH2)mNR4R5, (C3-C6)heterocycloalkyl m is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R4 and R5, the same or different, are selected from the group consisting of -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, all the other variables being as defined in claim 1, single enantiomers, diastereoisomers and mixtures thereof in any proportion and/or pharmaceutically acceptable salts and solvates thereof. 6. A compound according to Claim 5, wherein R2 is selected from tetrahydrofuranyl, dimethyltetrahydrofuranyl, oxetan-2-yl. 7. A compound of formula (I) according to Claim 1, wherein X1, X2, X3 and X4 are all CH or X2, is N and the others are CH; p is zero or 1; each R, when present, is F; R1 is 2-aminopyrimidin-4-yl; L is -C(O)NH- or -NHC(O)- ; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of -H, (C1-C6)alkyl which is methyl, propyl, isopropyl, tert-butyl, (C1-C6)hydroxyalkyl which is 2-hydroxy-2-methylpropyl, (C1-C6) alkoxy (C1-C6)alkyl which is 3-methoxypropyl, 2-ethoxyethyl, 3- isopropoxypropyl, 3-methoxy-3-methylbutyl, 2-methoxyethyl, 2-methoxy-2- methylpropyl, (C1-C6)haloalkyl which is 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoromethyl, 2-fluoro-2-methylpropyl, 3-fluoropropyl, 2,2- difluoropropyl, 3,3-difluoropropyl, (C1-C6)haloalkoxy (C1-C6)alkyl which is 3-(difluoromethoxy)propyl, (C3-C10)cycloalkyl which is cyclopropyl, cyclobutyl, Heteroaryl which is pyridinyl, and and (C3-C6)heterocycloalkyl which is azetidin-3-yl, piperidinyl, morpholinyl, 5- oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, each of which cycloalkyl, heteroaryl and heterocycloalkyl is in its turn optionally and independently substituted with one or more groups selected from halogen which is selected from F, Cl, Br, I, (C1-C6)alkyl which is methyl, tert-butyl, (C1-C6) alkoxy which is methoxy, (C1-C6) alkoxy (C1-C6)alkyl which is methoxymethyl, R6 and R7 are -H, single enantiomers, diastereoisomers and mixtures thereof in any proportion, or pharmaceutically acceptable salts and solvates thereof. 8. A compound according to claim 1 selected from: 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-cyclobutylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5,5-dimethyltetrahydrofuran-3-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-cyclopropylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-(piperidin-1-yl)ethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-(methoxy-d3)propyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-methoxypropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-methoxyethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3,3-difluorocyclobutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-isopropylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2,2,2-trifluoroethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(1-methylpiperidin-4-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-(difluoromethoxy)propyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-isopropoxypropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-morpholinopropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-hydroxy-2-methylpropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1s,3s)-3-methoxycyclobutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-((2R,6S)-2,6-dimethylpiperidin-1-yl)ethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-ethoxyethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-methylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(1-methylcyclopropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(1-(oxetan-3-yl)azetidin-3-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(cyclopropylmethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1s,3s)-3-(difluoromethoxy)cyclobutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-methoxy-2-methylpropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1-(methoxymethyl)cyclopropyl)methyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-fluoropropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1-methylcyclopropyl)methyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-fluoro-2-methylpropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1-(tert-butyl)-5-oxopyrrolidin-3-yl)methyl)benzamide (Enantiomer 1); 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1-(tert-butyl)-5-oxopyrrolidin-3-yl)methyl)benzamide (Enantiomer 2); 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((4-methylmorpholin-2-yl)methyl)benzamide (Enantiomer 1); 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((4-methylmorpholin-2-yl)methyl)benzamide (Enantiomer 2); 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3-methoxy-3-methylbutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1R,2S)-2-fluorocyclopropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(oxetan-2-ylmethyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(((1r,3r)-3-methoxycyclobutyl)methyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-propylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1r,3r)-3-methoxycyclobutyl)benzamide; (R)-3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2,2-difluoropropyl)benzamide; Trans 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-fluorocyclopropyl)benzamide (Enantiomer 1); Trans 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(2-fluorocyclopropyl)benzamide (Enantiomer 2); 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1S,2R)-2-fluorocyclopropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1s,3s)-3-fluorocyclobutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-((1r,3r)-3-fluorocyclobutyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(3,3-difluoropropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-methylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(3-methoxypropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide; 5-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(3-methoxypropyl)benzamide; 5-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-5-fluoro-N-methylbenzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-5-fluoro-N-(3-methoxypropyl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-4-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide; 3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-4-fluoro-N-(3-methoxypropyl)benzamide; 6-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)-N-methylpicolinamide; N-(3-(((7-(2-aminopyrimidin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4- yl)amino)methyl)phenyl)-4-methoxybutanamide; single enantiomers, diastereoisomers and mixtures thereof in any proportion, or pharmaceutically acceptable salts and solvates thereof. 9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carrier or excipient. 10. A pharmaceutical composition according to claim 9 suitable to be administered by inhalation, selected from inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. 11. A device comprising the pharmaceutical composition according to claim 10, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a soft mist nebulizer. 12. A pharmaceutical composition according to claim 9 suitable to be administered by oral route, selected from, gelcaps, capsules, caplets, granules, lozenges and bulk powders or aqueous and non-aqueous solutions, emulsions, suspensions, syrups, or elixirs formulations. 13. A compound or a pharmaceutical composition according to any one of claims 1 to 8 or 9 for use as a medicament. 14. A compound or a pharmaceutical composition for use according to claim 13, in the prevention and /or treatment of immune system disorders including Graft-versus- host disease (GVHD), and pulmonary diseases selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH). 15. A compound or a pharmaceutical composition according to claim 14 for use via oral route of administration particularly in the prevention and /or treatment of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and specifically Pulmonary Arterial Hypertension (PAH). 16. A combination of a compound as defined in any one of the claims 1 to 8 with one or more active ingredients selected from the classes consisting of organic nitrates and NO donors; inhaled NO; stimulator of soluble guanylate cyclase (sGC); prostaciclin analogue PGI2 and agonist of prostacyclin receptors; compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP); human neutrophilic elastase inhibitors; compounds inhibiting the signal transduction cascade; active substances for lowering blood pressure; neutral endopeptidase inhibitor; osmotic agents; ENaC blockers; anti- inflammatories including corticosteroids and antagonists of chemokine receptors; antihistamine drugs; anti-tussive drugs; antibiotics and DNase drug substance and selective cleavage agents; agents that inhibit ALK5 and/or ALK4 phosphorylation of Smad2 and Smad3; tryptophan hydroylase 1 (TPH1) inhibitors and multi-kinase inhibitors, beta2-agonists, corticosteroids, anticholinergic or antimuscarinic agents, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, leukotriene modulators, non- steroidal anti-inflammatory agents (NSAIDs), mucus regulators, mucolytics, expectorant/mucokinetic modulators, peptide mucolytics, inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma and combinations thereof.
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